KR20180118249A - Oncolytic adenovirus encoding a b7 protein - Google Patents

Abstract

The present disclosure relates to a clonogenic tumor cell-degrading adenovirus having selectivity for cancer cells, wherein the adenovirus comprises a transgene under the control of a promoter endogenous to the virus, wherein the transgene encodes a B7 protein or an active fragment thereof DNA sequences), compositions comprising them, methods of producing viruses, and uses of viruses and compositions in therapy, particularly in the treatment of cancer.

Description

Tumor cell disruption adenovirus encoding B7 protein {ONCOLYTIC ADENOVIRUS ENCODING A B7 PROTEIN}

The present disclosure provides an oncolytic adenovirus comprising a transgene encoding at least a B7 protein, such as CD80 or an active fragment thereof, in compositions and treatments comprising the same, in particular in the treatment of cancer. It relates to the use of viruses and compositions.

Cancer is still a great social burden on society in terms of the difficulties and sufferings of patients and their loved ones, and also in terms of the high economic costs of treating, caring for and supporting patients. It is now thought that the immune system of a healthy individual routinely eliminates cancerous cells. However, in patients with cancer, one or more of the defense mechanisms involved in this elimination are downregulated or completely degraded.

It is now known to alter its microenvironment to make a tumor more acceptable for its growth. This occurs, for example, by tumor-releasing extracellular signals, which promote tumor angiogenesis and/or induce local immune suppression or immune tolerance.

It is clear from many different preclinical and clinical studies that the microenvironment within a tumor can inhibit the development and activity of anti-tumor immune responses, and a wide variety of mechanisms have potentially been shown to play a role. In particular, immunosuppression mechanisms ultimately prevent T cell responses from mediating tumor cell death. Inhibitory mechanisms may include blocking T cells from entering tumor tissue, inhibiting activation of T cells entering the tumor, and modulating tumor cell proteins (reducing the ability of T cells to recognize or respond to it). . The importance of these immunosuppressive pathways in inhibiting tumor progression is by antibodies to receptors in two of these inhibitory pathways, CTLA4 and PD-1/PDL1, marketed for the treatment of melanoma and other cancers. It is particularly emphasized by the clinical efficacy shown.

B7, when paired with CD28 or CD152 (CTLA-4) surface protein on T cells, increases or decreases the activity of MHC-TCR signals between antigen presenting cells (APC) and T cells, respectively. It is a type of peripheral membrane protein found in activated antigen presenting cells (APCs) that can generate stimulus signals or co-inhibition signals. In addition to being presented on activated APCs, B7 can also be found on T cells themselves.

There are several steps involved in the activation of the immune system against the antigen. The T cell receptor must initially interact with a complex of its specific peptide antigen (Ag) bound to a major histocompatibility complex (MHC) surface protein. CD4 or CD8 proteins on the T cell surface interact with MHC, including both antigen binding chain dimers (alpha/beta or gamma/delta) and CD3 signaling complexes (including gamma, delta, epsilon and zeta chains). Helps stabilize the MHC/Ag interaction with the T cell receptor complex. This is also referred to as "signal 1", its main purpose is to provide initial signaling and to ensure antigen specificity of T cell activation.

However, MHC binding alone is insufficient to stimulate full effector T cell differentiation and activation. In fact, the lack of an additional stimulus signal can cause T cells to become energetic. The costimulatory signals necessary to allow the immune response to continue can come from the B7-CD28 and CD40-CD40L interactions. There are other activation signals that play a role in the immune response. For example, in the TNF family of molecules, protein 4-1BB (CD137) on T cells can bind to 4-1BBL on APC.

The B7 (CD80/B7-1 and/or CD86/B7-2) protein is present on the APC surface, which interacts with the CD28 receptor on the T cell surface. This is one source of "signal 2" (cytokines can also contribute to T cell activation, which can be referred to as "signal 3"). This interaction promotes differentiation into effector cells, which can mediate the survival, activation, and aspects of the immune response of target T cells, such as killing of viral infected cells or tumor cells, and recruitment of inflammatory cells. Produces a signal downstream of

Usually, to initiate a T cell response, a stimulus signal and a costimulatory signal are provided by antigen presenting cells to induce both CD4 and CD8 T cell responses. However, effector CD8 T cells recognize Ag associated with MHC type I molecules, presented in most nucleated cells, including tumor cells. However, the inventors have reason to believe that the signal for activating T cells does not have to come from the same cell or cell type. Thus, it would be useful to provide one or more of these signals (ie, a stimulus signal and/or a costimulatory signal) to the immune system, for example on the surface of a cancer cell.

Currently, as this pathway is thought to play an important role in down-regulating the immune response, for example in cancer, programmed cell death protein 1: programmed cell death protein 1 (PD-1) and/or its ligand PDL1 (also Known as B7-H1) activity.

However, some studies have shown that CD80 (B7-1) not only acts as a T cell co-stimulatory factor by binding to CD28 on T cells, but it also binds to PDL1, e.g. when expressed on the same cell membrane, and PDL1-PD1 It is proposed to be able to block inhibitory signaling interactions. Thus, by acting in two different ways, CD80 may be a viable and potentially more useful molecule to restore and augment activation of human T cells. The soluble form of CD80 also appears to be able to counter PDL1-PD1-mediated T cell inhibition, e.g., Haile et al Soluble CD80 Restores T Cell Activation and Overcomes Tumor Cell Programmed Death Ligand 1-Mediated Immune Suppression J Immunol 2013; 191:2829-2836]. The CD80-Fc fusion protein was generated and tested for safety and efficacy, see Journal of Immunology, 2014, 193: 3835-3841.

The inventors believe that, for example, on the surface of cancer cells, the B7 protein delivered and expressed by the tumor cell disruption virus, or an active fragment thereof, will be useful in activating the patient's own immune system to fight cancer.

Moreover, B7 proteins such as CD80, if simply administered systemically, have the potential to stimulate the immune response systemically in an undesirable manner. The inventors believe that more sophisticated delivery of this protein is needed to create a suitable therapeutic window in which advantageous therapeutic effects are realized and off-target effects are minimized.

Accordingly, a tumor cell disruption adenovirus having selectivity for cancer cells is provided, the adenovirus contains a transgene under the control of a promoter endogenous to the virus, and the transgene comprises a DNA sequence encoding the B7 protein or an active fragment thereof. Includes. This is advantageous because the tumor cell disruption protein according to the present disclosure preferentially infects cancer cells and thereby penetrates the microenvironment produced by the cancer. Once in a cancer cell, the B7 protein encoded by the virus can be expressed, for example, on the cell surface (ie, the cancer cell surface). This is advantageous because the B7 protein is in the desired position, which can then be biologically active.

In one embodiment, the encoded B7 protein comprises a sequence capable of immobilizing the protein on the surface of the cell, such as a transmembrane domain sequence, a GPI anchor, and the like.

Thus, in one embodiment, the cancer cell is infected with a protein of the present disclosure that specifically expresses the B7 protein or molecule on the surface of the cancer cell, and the B7 protein is at least a costimulatory signal, i.e., a signal 2 that activates a T cell. It is suitable to provide and/or can bind to and inhibit the activity of PD-L1 expressed on the surface of cancer cells or other cells in a local microenvironment.

In one embodiment, the B7 sequence comprises a transmembrane genetic element from a B7 protein, eg, a transmembrane genetic element native to a particular B7 protein, or a transmembrane domain from a B7 protein that is “different” to that specifically expressed.

The B7 protein is a surface expressed protein, and can also be used to carry the additional protein to the cancer cell surface, for example if at least the transmembrane domain of the B7 protein is attached to an additional protein.

Thus, in one embodiment, a replication competent tumor cell disruption adenovirus having selectivity for cancer cells is provided, wherein the adenovirus contains a transgene under the control of a promoter endogenous to the virus, and the transgene is B7 It includes a DNA sequence encoding a protein or an active fragment thereof.

A replicable tumor cell disruption virus according to claim 1 is also provided, wherein the B7 protein or active fragment thereof is B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7- It is independently selected from the group comprising H4, B7-H5 and B7-H6, in particular the B7 protein is B7-1 (CD80) or an active fragment thereof.

In one embodiment, the replicable tumor cell disruption virus is a group B adenovirus.

In one embodiment, the replicable tumor cell disruption virus is a chimeric virus.

In one embodiment, the replicable tumor cell disruption virus has a skeleton that is enadenotucirev (also referred to as EnAd).

In one embodiment, the replicable tumor cell disruption virus has the following formula (I):

5'ITR-B ₁ -B _A -B ₂ -B _X -B _B -B _Y -B ₃ -3'ITR (I)

B ₁ comprises E1A, E1B or E1A-E1B;

B _A is E2B-L1-L2-L3-E2A-L4;

B ₂ is binding or comprises E3 or a transgene, eg under an endogenous or exogenous promoter;

B _X is a DNA sequence comprising a binding or restriction site, one or more transgenes, or both;

B _B comprises L5;

B _Y contains a transgene encoding the B7 protein or an active fragment thereof;

B ₃ is a bond or includes E4.

In one embodiment, it is the replicable tumor cell disruption virus according to any one of claims 1 to 7, wherein the B7 protein or active fragment thereof is a transmembrane sequence, e.g., a transmembrane domain from a PDGF receptor, or It contains a GPI anchor suitable for immobilizing proteins or fragments on the cell membrane.

In one embodiment, the replicable tumor cell disruption virus is selected from the group comprising, for example, cytokines, chemokines, antagonistic antibody molecules or fragments thereof, and agonistic antibody molecules or fragments thereof. It further comprises a second transgene encoding the polypeptide.

In one embodiment, the second transgene and the third transgene are two selected from the group comprising, for example, cytokines, chemokines, antibodies, such as antagonistic antibody molecules or fragments thereof, or agonistic antibody molecules or fragments thereof. It encodes for different polypeptides.

In one embodiment, the second or third transgene is from the group comprising IL-2, IFN-alpha, IFN-beta, IFN-gamma, Flt3 ligand, GM-CSF, IL-15 and IL-12. Encrypts the selected cytokine.

In one embodiment, the second or third transgene is selected from the group comprising MIP1α, IL-8, CCL5, CCL17, CCL20, CCL22, CXCL9, CXCL10, CXCL11, CXCL13, CXCL12, CCL2, CCL19 and CCL21. Encrypts chemokines.

In one embodiment, the cytokine and chemokine combination is encoded by a virus selected from the group comprising Mip1α and Flt3 ligands and Mip1α and IFNα.

In one embodiment, the virus encodes, for example, an antibody molecule comprising a transmembrane sequence or a GPI anchor, or a fragment thereof, which is, for example, a transmembrane domain or cell membrane immobilized form from a PDGF receptor.

In one embodiment, the antibody molecule or binding fragment thereof comprises an anti-human CD3 antigen binding domain.

In one embodiment, the antibody molecule is an inhibitor selected from the group comprising, for example, an inhibitor of an angiogenic factor, such as an anti-VEGF antibody molecule, and an inhibitor of a T cell deactivation factor, such as an anti-CTLA-4 antibody molecule.

In one embodiment, the antibody molecule is, for example, one or more agents selected from the group comprising CD40, GITR, OX40, CD27 and 4-1BB.

In one embodiment, the exogenous protein or proteins encoded by the virus are in a form suitable for expression on the surface of a cancer cell.

Figure 1 Some of the important molecules involved in T cell recognition of antigen presenting cells or tumor cells, and some of the signaling events induced in responding T cells. The structure of PDL1 and its interaction with the IgV domain of PD1 are also illustrated.
2 shows some of the B7 family ligands and binding partners from the CD28 family of receptors.
Fig. 3 is Co-expressing human CD80 (Fig. 3a), co-expressing human IFNα and human CD80 (Fig. 3b), co-expressing OKT3 scFv and human CD80 (Fig. 3c), co-expressing human Flt3L, human MIP1α and human IFNα. (Fig. 3d), human Flt3L, human MIP1α and human CD80 co-expressing (Fig. 3e), human IFNα, human MIP1α and human CD80 co-expressing (Fig. 3f) a diagram of a transgene cassette for a virus, open reading frame (ORF) or OKT3 scFv (Fig. 3G).
Figure 4 Replication of EnAd (ColoAd1) and human CD80 encoding virus NG-330 in HT-29 (Figure 4A) and A549 (Figure 4B) tumor cells is shown.
5 is Expression of CD80 in the membrane of A549 (Fig. 5A) or HT-29 (Fig. 5B) tumor cells by fluorescent immunostaining at different times after infection with NG-330 is shown. No expression of CD80 on the cell membrane was observed by EnAd or uninfected tumor cells (UIC).
Fig. 6 is The HT-29 cytotoxicity assay shows comparable tumor cell disruption effects of EnAd and NG-330. Thus, NG-330 also retains its tumor cell decay properties while retaining the transgene.
Figure 7 shows the comparable tumor cell disruption potency of EnAd and CD80 + IFNα expressing NG-343 virus (Figure 7A) and secretion of IFNα by NG-343 infected HT-29 and A549 tumor cells over a period of up to 72 hours. .
Figure 8 shows the expression of CD80 and tumor cell death at 48 or 72 hours after infection by FACS analysis using anti-CD8 immunostaining with cell viability staining. CD80 could be detected on the cell surface of both live and dead NG-343 treated cells, not EnAd or uninfected control (UIC) A549 tumor cells (FIGS. 8A-D ). Similar CD80 expression was seen by both A549 and HT-29 tumor cells (FIG. 8E ).
9 is Shows comparable viral replication by both EnAd and NG-343 in tumor (HT-29) and non-tumor (MRC5, WI38 and bronchial epithelial cells) cells, the latter NG- detected only in HT-29 tumor cells. After 343 infection, it shows much lower levels of replication (Figure 9A), IFNα secretion (Figure 9B) and CD80 expression (Figure 9C).
10 shows, Compared to EnAd infected or uninfected tumor cell cultures, A549 tumor cells infected by NG-343 can induce increased surface levels of both CD80 and PD-L1 on the surface of DCs in PBMC cocultures. Show.
Fig. 11 is Expression of IFNa and CD80 by HT-29 (Fig. 11A-C) and A549 (Fig. 11B-C) tumor cells infected with NG-347 virus is shown.
12 is Expression of MIP1α (FIG. 12A ), IFNα (FIG. 12B) and Flt3L (FIG. 12C) by A549 tumor cells infected with NG-345 virus is shown.
Fig. 13 is The HT-29 cytotoxicity assay shows the comparable tumor cell disruption potency (Fig. 13A-B) and infectivity (Fig. 13C) of EnAd, NG-347 and NG-348 viruses.
14 shows high CD80 expression at 48 hours on the cell surface of A549 tumor cells infected with NG-347 or NG-348 virus, but little or no CD80 expression after EnAd infection.
15 shows high CD80 expression at 48 hours on the cell surface of DLD-1 tumor cells infected with NG-347 or NG-348 virus, but little or no CD80 expression after EnAd infection.
16 shows, It shows CD80 expression on ^{EpCam +} A549 cells infected by NG-348 and co-cultured with ^{human CD3 +} T cells, not when the infection was by EnAd.
Fig. 17 silver ^{It shows that CD25 is upregulated in human CD3 +} T cells after co-culture with NG-348 infected A549 cells, but no infection is by EnAd (Fig. 17A), and ^{the percentage of CD25 +} cells (Fig. 17B) and Both levels of CD25 expression per cell (FIG. 17C) were increased.
Fig. 18 is The CD4 ⁺ CD25 and CD4 then cocultured with NG-348 infected A549 ^cells (primarily CD8) up-regulated in both human CD3 ⁺ T cell subpopulation, but shows that when the infection is EnAd.
19 shows low levels of HLA-DR expression on ^{human CD3 +} T cells after co-culture with NG-348 or EnAd infected A549 cells.
Fig. 20 is Live after co-culture with NG-348 infected A549 cells ^{, induction of CD107a expression on the surface of CD3 +} T cells, but shows that the infection is absent by EnAd.
Fig. 21 is ^{Induction of CD107a expression in both CD4 +} and CD4 ^- CD3 ⁺ T cell subpopulations after co-culture with NG-348 infected A549 cells, but shows that the infection is absent by EnAd.
Figure 22 Induction of IL-2 (FIG. 22A) and IFNγ (FIG. 22B) production by ^{CD3 +} T cells after co-culture with NG-348 infected A549 cells, but when the infection was by EnAd, IL-2 and only low Shows the level of IFNγ.
FIG. 23 ^{shows the induction of IFNγ production by both CD4 +} and CD8 ⁺ CD3 ⁺ T cells after co-culture with NG-348 infected A549 cells (FIG. 22B ), but when the infection was by EnAd, it was unintended (CD4 ⁺ cells. ) Or low (CD8 ⁺ cells) IFNγ.
24 shows, It shows that CD69 is upregulated in ^{more human CD3 +} T cells after co-culture with NG-347 infected A549 cells than when infection is by EnAd.
25 shows, It shows the induction of IFNγ production by ^{human CD3 +} T cells after co-culture with NG-347 infected A549 cells, not when infection is by EnAd.
Fig. 26 is Schematic of the NG-348A, NG-420 and NG-420A transgene cassettes is shown.
Figure 27 shows genomic replication and hexon gene expression (mRNA levels) for EnAd, NG-347 and NG-348 in MRC-5 fibroblast cells compared to A549 tumor cells.
Figure 28 shows CD80 and anti-CD3-scFv transgene mRNA and CD80 transgene protein (flow cytometry) expression against virus NG-348 in MRC-5 fibroblast cells compared to A549 tumor cells.
29 shows CD80 transgene mRNA and CD80 transgene protein for virus NG-347 in MRC-5 fibroblast cells compared to A549 tumor cells.
30 shows, The mRNA and secreted protein levels of MIP1α and IFNα produced by virus NG-347 in MRC-5 fibroblast cells compared to A549 tumor cells are shown.
31 shows genomic replication and hexon gene expression (mRNA level) for EnAd, NG-347 and NG-348 in purified human T cell culture.
FIG. 32 shows CD80 and anti-CD3 scFv transgene mRNA and protein expression (flow cytometry) against virus NG-348 in human T cells compared to A549 tumor cells.
Figure 33 shows CD80 transgene mRNA and CD80 transgene protein for virus NG-347 in purified human T cells compared to A549 tumor cells.
34 shows, Shows the IFNα and MIP1α transgenes produced by virus NG-347 in T cells, compared to A549 tumor cells.
35 shows, Compared to A549 tumor cells, NG-347 and NG-348 genome replication and hexon gene expression by human PBMCs are shown.
36 shows, Compared to A549 tumor cells, CD80 and anti-CD3 scFv mRNAs produced by virus NG-348 by PBMCs are shown.
37 shows, Compared to A549 tumor cells, CD80, IFNα and MIP1α mRNA produced by virus NG-347 by PBMCs are shown.
Figure 38 shows similar activation of human dendritic cells by EnAd, NG-347 and NG-348 virus particles, as measured by downregulation of CD14 expression and upregulation of CD80 on the cell surface.
39 shows similar particle mediated MIP1α and IFNα protein secretion from PBMCs cultured with NG-348(A) or NG-347(B) compared to EnAd.
Figure 40 , NG-347 or NG-348 genome replication in co-culture or T cells or PBMC and MRC-5 fibroblast cells compared to co-culture with A549 tumor cells.
Figure 41 shows INFγ secreted by PBMC or T cells co-cultured with MRC-5 fibroblast cells and treated with EnAd or virus NG-348 compared to A549 tumor cells.
42 shows MIP1α and IFNα secreted by human dendritic cells treated with EnAd, NG-347 or NG-348 virus particles.
Figure 43 Silver NF-κB and IFN reporter gene activation generated by JurkatDual reporter T cells co-cultured with EnAd, NG-347 or NG-348 infected A549 tumor cells.
Figure 44 shows the NF-κB-luciferase reporter activity produced by JurkatDual reporter T cells co-cultured with EnAd, NG-347, NG-348 or NG-420 treated A549 HCT-116, DLD and HT29 tumor cells. .
Figure 45 shows the NF-κB-luciferase reporter activity produced by JurkatDual cells co-cultured with A549 or HT29 tumor cells infected with virus NG-348 and virus NG-420 as a function of added viral particles.
Figure 46 is the pharmacokinetics of EnAd and virus NG-348 in blood; Blood cytokine levels after exposure to EnAd or virus NG-348; The tissue biodistribution of EnAd or NG-348 virus is shown at 6 or 24 hours after IV administration to CD1 mice.
Figure 47 shows the pharmacokinetics of EnAd, NG-347 and NG-348 viruses in blood after IV administration to CB17-SCID mice bearing subcutaneous HCT-116 tumor xenografts.
Figure 48 is the tissue distribution of EnAd, NG-347 and NG-348 virus 6 hours after intravenous dosing in tumor bearing CB17-SCID mice, and after intravenous or intratumoral dosing of EnAd, NG-347 and NG-348. Viral genomes in HCT-116 tumor xenografts are shown on days 7 or 14-21.
Figure 49 shows viral hexon mRNA generated in HCT-116 tumor xenografts with EnAd, NG-347 or NG-348 virus 7 days or 14-21 days after intravenous or intratumoral dosing.
Figure 50 shows the mRNA levels for hexon and CD80 transgenes in HCT-116 tumor xenografts 7 or 21 days after intravenous dosing with virus NG-348.
Figure 51 shows the mRNA levels for the transgene encoding anti-CD3 ScFv and CD80 in HCT-116 tumor xenografts 7 days or 14-21 days after IV dosing with virus NG-348.
Figure 52 shows the mRNA levels of MIP1α and IFNα transgenes in HCT-116 tumor xenografts at 7 days or 14-21 days after intravenous dosing with virus NG-347.
Figure 53 shows CD80 protein expression in HCT-116 tumor xenografts 7 and 21 days after intravenous dosing of virus NG-348; MIP1α and CD80 protein expression in HCT-116 tumors after intravenous dosing of virus NG-347 is shown.
Summary of Sequence Listing
_{SEQ ID NO: 1 shows a B Y} DNA sequence comprising bp 29345-29379 of the EnAd genome and corresponding thereto.
SEQ ID NO: 2 PDGF TM domain
SEQ ID NO: 3 splice acceptor sequence
SEQ ID NO: 4 splice acceptor sequence
SEQ ID NO: 5 poly adenylation sequence (SV40 late polyA sequence)
SEQ ID NO: 6 Internal Ribosome Entry Sequence (IRS)
SEQ ID NO: 7 High efficiency self-cleavable P2A peptide sequence
SEQ ID NO: 8 High-efficiency self-cleavable F2A peptide sequence
SEQ ID NO: 9 High efficiency self-cleavable E2A peptide sequence
SEQ ID NO: 10 High efficiency self-cleavable T2A peptide sequence
SEQ ID NO: 11 human CD80 amino acid sequence
SEQ ID NO: 12 human interferon amino acid sequence
SEQ ID NO: 13 human soluble Flt3 ligand amino acid sequence
SEQ ID NO: 14 Human macrophage inflammatory protein 1a amino acid sequence (LD78b isoform)
SEQ ID NO: 15 Membrane immobilized form of anti-human CD3 single chain Fv
SEQ ID NO: 16 NG-330 viral genome sequence comprising the EnAd genome, having a transgene cassette encoding a T lymphocyte activating antigen, which is CD80 inserted in _{region B Y.} The transgene cassette contains a 5'SSA, a human CD80 cDNA sequence and a 3'poly(A).
NG-343 viral genome sequence comprising EnAd genome, having a transgene cassette encoding IFNa and CD80 inserted in SEQ ID NO: 17 region B _Y. The transgene cassette contains 5'SSA, IFNa cDNA sequence, P2A peptide, CD80 cDNA sequence and 3'poly(A).
NG-345 viral genome sequence comprising the EnAd genome, having a transgene cassette encoding an Flt3 ligand, MIP1a and IFNα inserted in the _{region B Y} of SEQ ID NO: 18. The transgene cassette contains 5'SSA, Flt3 ligand cDNA, P2A peptide sequence, MIP1a cDNA sequence.
NG-346 viral genome sequence comprising EnAd genome, having a transgene cassette encoding Flt3 ligand, MIP1a and CD80 inserted in SEQ ID NO: 19 region B _Y. The transgene cassette contains 5'SSA, Flt3 ligand cDNA sequence, P2A peptide sequence, MIP1a cDNA.
SEQ ID NO: 20 NG-347 viral genome sequence comprising an EnAd genome having a transgene cassette encoding IFNα, MIP1α and CD80 inserted in _{region B Y.} The transgene cassette contains 5'SSA, IFNα cDNA sequence, P2A peptide sequence, MIP1α cDNA sequence, T2A.
SEQ ID NO: 21 EnAd genome
SEQ ID NO: 22 E2B region of EnAd genome (BP 10355-5068)
SEQ ID NO: 23 E3 region from EnAd
Non-coding sequence for inclusion with SEQ ID NO: 24 B _X
Non-coding sequence for inclusion as SEQ ID NO: 25 B _Y
SEQ ID NO: 26-34 hinge linker sequence
SEQ ID NO: 35-74 flexible linker sequence
SEQ ID NO: 75 and 76 rigid linker sequence
SEQ ID NO: 77-90 linker sequence
SEQ ID NO: 91 PDGFR receptor A
SEQ ID NO: 92 PDGFR receptor B
SEQ ID NO: 93 Insulin-like growth factor 1
SEQ ID NO: 94 IL6-R
SEQ ID NO: 95 CD28
NG-348 viral genome sequence comprising the EnAd genome, having a transgene cassette encoding the membrane-immobilized chimeric form of a T lymphocyte activating antigen, which is a single chain Fv anti-human CD3e and CD80 inserted in the _{region B Y} of SEQ ID NO: 96.
SEQ ID NO: 97 nucleic acid encoding membrane tethered OKT3-scFv
SEQ ID NO: 98 Transgene cassette sequence for NG-348
SEQ ID NO: 99 Membrane immobilized form of anti-human CD3 scFv with C-terminal V5 tag
SEQ ID NO: 100 V5 tag (9 amino acid variant)
NG-348A virus comprising the EnAd genome, having a transgene cassette encoding a membrane-immobilized chimeric form of a single-chain Fv anti-human CD3e and CD80 inserted in SEQ ID NO: 101 region B _Y Genomic sequence.
SEQ ID NO: 102 NG-420 viral genome sequence comprising the EnAd genome, having a transgene cassette encoding a membrane-immobilized chimeric form of single-chain Fv anti-human CD3e inserted in _{region B Y.} The transgene cassette contains 5'SSA.
SEQ ID NO: 103 NG-420A viral genome sequence comprising EnAd genome, having a membrane immobilized chimeric form of single-chain Fv anti-human CD3e inserted in _{region B Y and a transgene cassette encoding a C-terminal V5 tag.} It contains a transgene cassette.
SEQ ID NO: 104 linker
SEQ ID NO: 105 Sequence comprising the start codon
SEQ ID NO: 106 c-myc tag
SEQ ID NO: 107 c-myc tag with amino acid spacers at N and C termini
SEQ ID NO: 108 spacer-c-myc tag-spacer PDGF TM domain
Fully synthetic EnAd genome with incorporated cloning site for transgene cassette insertion as in SEQ ID NO: 109 plasmid pEnAd2.4

B7 is a family of proteins.

Since the extracellular domains of protein family members generally regulate biological functions, the B7 protein encoded in the tumor cell disruption proteins of the present disclosure may be useful, e.g., the B7-1 extracellular domain primes T cells or Can be used to stimulate. The actual biological function is specific to the extracellular domain of each given B7 protein (ie, generally different protein members of the B7 family have different functions). Other functions of the B7 protein, such as B7-1 and/or B7-2, may include the ability to bind to CD28 and/or CTLA-4, in particular to signal or activate the relevant signaling cascade or cascades.

Additionally or alternatively, the transmembrane domain of the B7 protein can be used to direct the protein encoded by the protein of the present disclosure to the surface of the cancer cell, for example by fusing the transmembrane domain to the C terminus of the relevant protein. I can.

B7 protein, as used herein, unless the context indicates otherwise, the full-length sequence of a protein from the B7 family or at least 95% similar or identical thereto (e.g., 96% with this along all of the relevant sequences. , 97%, 98%, 99% or 100% similar or identical). The B7 family includes B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6, B7-H7. When a full-length protein is used, there will generally be at least one normal biological function of the protein.

As used in connection with the B7 family, the full-length protein refers to at least the extracellular domain comprising the chimeric B7 protein, the sequence of the chimera has the structure and function of the B7 protein, and the sequence constituting the chimera is from the protein in the B7 family. Is selected. The genetic element in a fragment or full-length B7 protein may be from the same or different B7 protein. Thus, in one embodiment, the B7 fragment or protein is chimeric.

The chimeric B7 protein, as used herein, is when substantially all of the sequences constituting the chimera are derived from the B7 protein, e.g., a fragment of the B7 protein in which at least 98% of the sequence of the chimeric are fused together. Thus, chimeric fragment, as used herein, refers to a fragment comprising sequences from two or more different B7 proteins.

In one embodiment, the full length B7 protein comprises an extracellular domain, for example from a single B7 protein, such as B7-1 and/or B7-2.

In one embodiment, the full-length B7 protein is an extracellular domain and a transmembrane domain, e.g., from the same B7 protein, or alternatively an extracellular domain and completely from a B7 protein (e.g., B7-1 and/or B7-2). Transmembrane domains or equivalents from different proteins, such as lipid membrane anchors.

In one embodiment, the full length chimeric B7 protein may comprise an extracellular domain of one B7 protein (eg, B7-1 and/or B7-2) and a transmembrane domain from a different B7 protein.

In one embodiment, the full length B7 protein comprises an extracellular domain, a transmembrane domain and an intracellular domain, eg, all from the same B7 protein or two or more different B7 proteins.

The active fragment of the B7 protein, as used herein, refers to a fragment having at least one function of the B7 protein, for example to promote expression on the surface of cancer cells or other biological functions of the B7 protein.

In one embodiment, the fragment has at least 50% of the activity of the full-length protein, such as 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% of the activity of the full-length protein. .

In one embodiment, the active fragment comprises or consists of a B7 extracellular domain or a sequence that is at least 95% similar or identical, such as 96%, 97%, 98%, 99% or 100% similar or identical to the B7 extracellular domain.

In one embodiment, the B7 fragment comprises or consists of a B7 protein, particularly a transmembrane domain from one described herein, such as B7-1. It is believed that the use of the latter contributes to the expression on the cell surface.

In one embodiment, the active B7 fragment may be part of an extracellular domain.

Active fragments, such as transmembrane fragments or larger fragments comprising more B7 domains, can be used in fusion proteins with additional proteins, for example to facilitate expression of additional proteins on the surface of cancer cells.

Larger fragments, as used herein, do not specifically mean size or weight, and in turn mean a larger repertoire of sequence information that can provide more functionality (i.e., fragments have at least two B7 Including sequences from domains).

In one embodiment, the larger fragment comprises several biological activities of the related B7 protein. In one embodiment, the active B7 fragment is a fragment that retains the essential biological activity of a full-length protein, eg, the ability to prime or activate T cells.

The activity of a given protein fragment can be assayed in relevant in vitro assays, e.g., using the assay described in the Examples herein, e.g., using the full length protein as a comparator. When the active fragment is a transmembrane domain, the activity can be assessed, for example, by analyzing the surface expression on cells of the relevant protein to which the transmembrane domain is attached using the assay described in the Examples herein.

When the full-length B7 protein is part of a fusion protein, the B7 moiety may be linked to an additional protein by an amide bond between the end of one sequence and the start of the next protein sequence, or may be linked by a linker. Examples of linkers are provided below.

The full-length B7 protein comprising the transmembrane domain can be used to present the B7 protein and the extracellular domain of the protein or fragment, fused or linked thereto on the surface of the infected cancer cell. Generally, in this embodiment, the B7 protein will attach to the surface of the cancer cell, and the “other” protein will be on the extracellular side and at the N-terminus of the cancer cell surface.

Even so, the protein can be arranged as desired, for example with the B7 extracellular domain at the N terminus, fused or linked to the next protein or fragment, at the C terminus, which in turn is a transmembrane domain at the C terminus, for example It is fused or linked to a transmembrane domain from the B7 protein.

In general, when the full length B7 protein is used in the fusion protein, both the B7 protein and the additional protein will have a biological function.

Fusion protein, as used herein, refers to at least two proteins or fragments or a combination of at least one protein and at least one fragment fused directly or linked to each other, for example by a linker.

Fusion, as used herein, generally refers to an amide bond between the end of one polypeptide (or protein/fragment) and the beginning of the next polypeptide (or protein/fragment).

Linkage refers to a case where two aggregates, such as two polypeptide sequences, are linked through a linker, unless the context indicates otherwise. A linker is a sequence that is not naturally present in either the polypeptide or sequence, which is not present at that particular position for both polypeptides.

In one embodiment, the fusion protein comprises a B7 protein or an active fragment thereof. Fusion proteins and additional proteins, including B7 fragments or proteins, are not referred to herein as chimeric proteins. In general, fusion protein, as used herein, refers to a combination of a B7 protein or fragment thereof and another non-B7-protein/fragment.

The only proteins containing fragments from different B7 proteins are referred to herein as chimeras as described above.

In one embodiment, the fusion protein of the present disclosure does not comprise the B7 protein or an active fragment thereof, but is encoded by a protein of the present disclosure other than the B7 protein or fragment thereof.

Thus, proteins of the present disclosure may encode aggregates other than the B7 protein or an active fragment thereof, and such aggregates include additional proteins.

B7 family

In one embodiment, B7 is B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6, B7-H7, their activity Fragments, and combinations thereof. In one embodiment, the B7 protein is B7-1 (CD80), B7-2 (CD86) or any active fragments thereof and combinations thereof, particularly B7-1 or active fragments thereof.

B7 proteins include B7-1 (also known as CD80 uniprot number P33681), B7-2 (also known as CD86 uniprot number P42081). This protein binds to CD28 and CTLA-4.

In one embodiment, the CD80 has the following sequence:

MGHTRRQGTSPSKCPYLNFFQLLVLAGLSHFCSGVIHVTKEVKEVATLSCGHNVSVEELAQTRIYWQKEKKMVLTMMSGDMNIWPEYKNRTIFDITNNLSIVILALRPSDEGTYECVVLKYEKDAFKREHLAEVTLSVKADFPTPSISDFEIPTSNIRRIICSTSGGFPEPHLSWLENGEELNAINTTVSQDPETELYAVSSKLDFNMTTNHSFMCLIKYGHLRVNQTFNWNTTKQEHFPDNLLPSWAITLISVNGIFVICCLTYCFAPRCRERRRNERLRRESVRPV SEQ ID NO: 11

Other B7 proteins include B7-DC (also known as PDCD1LG2 and PD-L2 Uniprot number Q9BQ51), B7-H1 (also known as PD-L1 and CD274: Uniprot number Q9NZQ7). Both of these proteins bind to PD-1.

Programmed death-ligand 1 (PD-L1) is a 40 kDa type 1 transmembrane protein that is believed to play an important role in suppressing the immune system. It appears that upregulation of PD-L1 may allow cancer to evade the host immune system. Analysis of 196 tumor specimens from patients with renal cell carcinoma revealed that high tumor expression of PD-L1 was associated with increased tumor aggressiveness and a 4.5-fold increased risk of death. Ovarian cancer patients with higher expression of PD-L1 had significantly poorer prognosis than patients with lower expression. PD-L1 expression is inversely correlated with the number of CD8+ T-lymphocytes in the epithelium, suggesting that PD-L1 on tumor cells can inhibit anti-tumor CD8+ T cells. The effect will be tumor type dependent; Studies in patients with non-small cell lung cancer have shown that higher PD-L1 protein and mRNA expression is associated with increased local lymphocyte affinity and longer survival. A number of anti-PDL1 antibodies have been shown to be of significant benefit for the treatment of several cancers in clinical trials.

In one embodiment, the B7-DC and/or B7-H1 protein or fragment thereof used in the proteins of the present disclosure is mutated so as not to stimulate immune suppression, eg, to eliminate immune suppression functions.

Alternatively, viruses encoding the non-mutated form of the B7-H1 extracellular domain can be used to treat appropriate cancers, and upregulation of PD-L1 is associated with a good/improved prognosis, such as lung cancer.

In one embodiment, at least the cytoplasm (intracellular domain) of B7-DC and/or B7-H1 is deleted or non-functional. Without wishing to be bound by theory, there is evidence to suggest that removal of the intracellular domain reduces cancer cell resistance to lysis [Blood 2008, April 1; 111(7) 3635-3643].

In one embodiment, only the transmembrane domain fragment of B7-DC and/or B7-H1 is used. In one embodiment, the following proteins are not provided as full-length proteins B7-DC and B7-H1 with associated biological activity.

Other B7 proteins are B7-H2 that binds ICOS (also known as ICOSLG, B7RP1, CD275: Uniprot No. O75144), B7-H3 that binds NKp30 (also known as CD276: Uniprot No. Q5ZPR3), B7- H4 (also known as VTCN1: Uniprot number Q727D3), B7-H5 (also known as VISTA, platelet receptor Gi24, SISP1), B7-H6 (also known as NCR3LG1, NR3L1), B7- binding to CD28H H7 (also known as HHLA2).

In one embodiment, the fragment comprises only any one of the transmembrane domains of B7-H2, B7-H3, B7-H4, B7-H5, B7-H6 and B7-H7.

Individual proteins include single proteins, which are proteins or active fragments thereof that are not part of a fusion protein (including chimeric proteins), and also fusion proteins. In one embodiment, the individual proteins are single proteins (including active fragments thereof).

In one embodiment, the cytoplasmic domain of the B7 protein is present. In one embodiment, the cytoplasmic domain is absent. The absence of a cytoplasmic domain can reduce or eliminate intracellular signaling to cancer cells, pertaining to one or more of the embodiments described below.

" Transmembrane domain"

In one embodiment, a transmembrane domain other than that derived from the B7 protein is used to express a protein (including a fusion protein) encoded by a protein of the present disclosure on the surface of an infected cancer cell, e.g., a transmembrane domain. Can be used to present an active B7 protein fragment or another protein of interest on the surface of infected cancer cells. Alternatively, it can be used to present on the surface a fusion protein comprising, for example, a B7 protein or an active fragment thereof. In one embodiment, the transmembrane domain from the PDGF receptor or fragment thereof is used to express B7 and/or another protein on the cancer cell surface.

In one embodiment, the transmembrane tether or anchor sequence used in the present disclosure comprises a PDGFR™ domain (e.g., ala513-arg561), such as AVGQDTQEVIVVPHSLPFKVVVISAILALVVLTIISLIILIMLWQKPR ( SEQ ID NO: 2 ) .

In one embodiment, the tether or anchor sequence used in the present disclosure comprises a tag attached to, for example, a PDGF receptor or fragment thereof, such as a PDGFR™ domain, in particular SEQ ID NO: 2.

Suitable tags include His-tag, Flag-tag, c-myc tag, and the like. More specifically, the tether or anchor may comprise, for example, the c-myc tag of SEQ ID NO: 106 EQKLI seed L, followed by the PDGFR TM domain described in SEQ ID NO: 2 AVGQDTQEVIVVPHSLPFKVVVISAILALVVLTIISLIILIMLWQKKPR (eg, ala513-arg561) do.

In one embodiment, the c-myc tag comprises a spacer or spacer amino acid, e.g., gsEQKLISEEDLn ( SEQ ID NO: 107 , where lowercase letters indicate amino acids added to the tag as spacers) at the 3'and/or 5'ends.

In one embodiment, the tether or anchor sequence used is g sEQKLISEEDLnAVGQDTQEVIVVPHSLPFKVVVISAILALVVLTIISLIILIMLWQKKPR ( SEQ ID NO: 108 ), where lowercase letters represent amino acid spacers .

In general, tethered or anchored proteins/polypeptides do not contain stop codons.

Exogenous proteins or proteins encoded by a virus according to the present disclosure will generally comprise a leader sequence (also referred to as a signal peptide). The leader sequence is, for example, a sequence of about 5 to 30 amino acids in length located at the N-terminus of a protein or polypeptide.

In one embodiment, the leader sequence for a protein expressed on the surface of a cancer cell is human, eg, HuVHSS.

In one embodiment, the structure of the ORF cassette is as follows:

LS-POLY-TAG-TM_D

In the formula,

LS is a leader sequence, eg, a human leader sequence;

POLY is a polynucleotide encoding a polypeptide or protein of interest, particularly those disclosed herein;

TAG is a tag, for example one disclosed herein, such as c-myc, in particular SEQ ID NO: 100 or 106;

TM_D is a TM domain, eg PDGFR TM domain, eg SEQ ID NO: 2.

When the polypeptide is an scFv, the ORF can be as follows:

LS-VAR ₁ -LINK-VAR ₂ -TAG-TM_D

In the formula,

LS is a leader sequence, eg, a human leader sequence;

VAR ₁ is a polynucleotide encoding a variable region, such as a VH region;

LINK is, for example, a linker as disclosed herein, such as a linker based on units of _{G 4} S, in particular SEQ ID NO: 104 GGGGSGGGGSGGGGS;

VAR ₂ is a polynucleotide encoding a variable region, such as a VL region;

TAG is a tag, for example one disclosed herein, such as c-myc, in particular SEQ ID NO: 100 or 106 ;

TM_D is a TM domain, eg PDGFR TM domain, eg SEQ ID NO: 2 .

The present disclosure also extends to embodiments, particularly those specifically described herein, comprising a tag at the N or C terminus of the polypeptide chain (wherein it is inside or outside the membrane). Thus, a C-terminal tag located inside the membrane is advantageous, because it probably does not interfere with the binding or function of the polypeptide.

Even so, expressing the tag at the N-terminus of a surface-expressed protein can be useful in some situations, as it can facilitate the isolation, identification and purification of cells expressing the protein.

In one embodiment, the combination of the transmembrane domain and secretory signal sequence is used to express the protein encoded by the virus (eg, as described herein) on the surface of the infected cancer cell. The present inventors have found that the encoded protein is expressed only on cells that are acceptable to infection by tumor cell disruption viruses, that is, cancer cells.

In one embodiment, a fragment used to express a protein on the surface of an infected cancer cell (e.g., a transmembrane fragment) is, for example, a PDGF receptor, insulin-like growth factor receptor, IL-6 receptor, CD28, glycoporin, It is selected from about 20 to 25 hydrophobic amino acids that form a transmembrane alpha helix from proteins including the LDL receptor, influenza HA protein, insulin receptor, asialoglycoprotein receptor, and transferrin receptor.

In one embodiment, the fragment (e.g., transmembrane fragment) used to express the protein on the surface of the infected cancer cell comprises the TM domain sequence (minimum portion) provided in SEQ ID NO: 91 , 92 , 93 , 94 or 95. Is selected from the group:

In one embodiment, the transmembrane domain used is from an S antigen or G protein coupled receptor from hepatitis B.

In one embodiment, the fusion protein comprising the full-length extracellular domain or fragment of the B7 protein and also a transmembrane domain derived from a protein other than B7, is such that the B7 protein is located at the terminal end of the fusion protein distal from the cancer cell surface, That is, they are arranged so as to be outside of the cancer cells in contact with the extracellular space.

virus

It is also advantageous to have a DNA sequence encoding the B7 protein or active fragment under the control of an endogenous promoter, since the protein is expressed along the viral life cycle as opposed to constitutively expressed. In this context, continuous expression under a strong promoter such as an exogenous promoter, for example the CMV promoter, can produce more B7 protein than is required for a therapeutic effect and can lead to off-target effects.

Alternatives to the transmembrane domain for expressing proteins on the surface of infected cancer cells include approaches using glycophospholipid anchors (also referred to as GPI anchors) attached to the C-terminal amino acids of extracellular proteins or fragments ( Low et al 1986, Cross 1987, Low and Saltiel 1988, Ferguson and William 1988). Suitable glycophospholipid anchors for use in the present disclosure include those from Thy-1, N-CAM and DAF.

In one embodiment, the tumor cell disruption virus according to the present disclosure is an adenovirus, eg, a group B adenovirus. In one embodiment, the protein according to the present disclosure is a chimeric virus, eg EnAd. In one embodiment, the adenovirus is replicable.

In one embodiment, the virus is replication defective and is provided as a viral vector.

In one embodiment, the sequence encoding the B7 protein or active fragment thereof is located between the stop codon and polyA recognition site of adenovirus gene L5 and the stop codon and polyA recognition site of gene E4.

In one embodiment, the sequence encoding the B7 protein or active fragment thereof is located between, or equivalent to, about bp 29356 and about 29357 of the EnAd genome, for example as set forth in SEQ ID NO: 21. The skilled artisan will understand that the absolute numeric value of a location can vary based on how the numbering is assigned. However, the relative position of the inserted gene remains the same regardless of the absolute numeric value used.

In one embodiment, the tumor cell disruption adenovirus according to the present disclosure has the following formula (I) :

5'ITR-B ₁ -B _A -B ₂ -B _X -B _B -B _Y -B ₃ -3'ITR (I)

In the formula,

B ₁ is a bond or comprises E1A, E1B or E1A-E1B (particularly E1A, E1B or E1A-E1B);

B _A is E2B-L1-L2-L3-E2A-L4;

B ₂ is binding or comprises E3 or a transgene, eg under an endogenous or exogenous promoter;

B _X is a DNA sequence comprising a binding or restriction site, one or more transgenes, or both;

B _B comprises L5;

B _Y contains a transgene encoding the B7 protein or an active fragment thereof;

B ₃ is a bond or includes E4.

In one embodiment, the tumor cell disruption virus has the following formula ( la ) :

5'ITR-B ₁ -B _A -B ₂ -B _B -B _Y -B ₃ -3'ITR (Ia)

In the formula,

B ₁ is a bond or comprises E1A, E1B or E1A-E1B (particularly E1A, E1B or E1A-E1B);

B _A is E2B-L1-L2-L3-E2A-L4;

B ₂ is a bond or contains E3;

B _B comprises L5;

B _Y contains a transgene encoding the B7 protein or an active fragment thereof;

B ₃ is a bond or includes E4.

In one embodiment , the viral genome in the construct of formula (I ) and/or ( Ia ) is from Ad11 or EnAd, particularly EnAd.

In one embodiment, the transgene encoding the B7 protein or active fragment thereof is under the control of an endogenous promoter, eg, a major late promoter.

Regulating element

In one embodiment B _Y comprises a transgene cassette, said cassette comprising a combination of a transgene encoding the B7 protein or a fragment thereof and a regulatory element, such as a regulatory element.

In one embodiment, the regulatory element is a splice acceptor sequence.

In one embodiment, the regulatory element is a Kozak sequence.

In one embodiment, for example, when the transgene encodes a polycistronic RNA molecule, the regulatory element is an IRES sequence.

In one embodiment, the regulatory sequence is a highly efficient self-cleavable peptide sequence, such as P2A, T2A, F2A, E2A.

In one embodiment, the regulatory sequence is a polyA tail.

In one embodiment, at least two regulatory sequences are present, e.g., a splice acceptor and a Kozak sequence or a splice acceptor and a polyA tail, or a splice acceptor and an IRES sequence, or a splice acceptor and a P2A sequence. do.

In one embodiment, at least three modulator sequences, such as a splice acceptor sequence, a Kozak sequence and a polyA tail, or a splice acceptor sequence IRES or 2A sequence and a polyA tail; Or a splice acceptor sequence, a Kozak sequence and an IRES or 2A sequence.

In one embodiment, at least four regulatory sequences, e.g., splice acceptor sequences, Kozak, located in the order of the splice acceptor sequence, Kozak sequence, IRES or 2A sequence and the polyA tail, particularly between L5 and E4. Sequence, IRES or 2A sequence and polyA tail.

In one embodiment, the transgene encodes a polycistronic RNA molecule comprising both IRES and 2A regulatory sequences.

Proteins encoded by viruses

In one embodiment, a protein of the present disclosure encodes a plurality of proteins for expression on the surface of an infected cancer cell, wherein at least one is a B7 protein or an active fragment thereof, e.g., 2, 3, 4 The above different proteins are encoded, in particular two or three proteins are encoded by the virus for expression on the surface of cancer cells or secretion into the extracellular space. Proteins include fusion proteins in this context. In one embodiment, a protein of the present disclosure encodes two different B7 proteins, active fragments thereof, or a combination thereof, e.g., both, for expression on the surface of cancer cells.

In one embodiment, the protein according to the present disclosure is one or two proteins for cell surface expression, and secretion/release from or intended to act with, for example, cancer cells that cannot be immobilized on the cell surface. Encodes one or two proteins for.

In one embodiment, the B7 protein or active fragment is encoded by a protein of the present disclosure for expression on the surface of a cancer cell, and released or secreted from the cell, of the same B7 protein or a different B7 protein (including the active fragment), The soluble form is also encoded by the virus.

In one embodiment, at least two different B7 proteins or active fragments are encoded by the proteins of the present disclosure.

In one embodiment, at least one protein expressed on the cell surface is a B7 protein, and at least one cell non-immobilized (eg, secreted) protein is a non-B7 protein.

In one embodiment, multiple proteins can be encoded to be expressed as separate proteins that are independently processed and expressed on the cancer cell membrane. The independence of proteins on the surface of cancer cells can make a positive contribution to immune activation. Without wishing to be bound by theory, lipid packing can affect the fluidity (ie, viscosity) of the lipid bilayer in the membrane of cancer cells. The viscosity of the membrane can affect the rotation and orientation of proteins and other biomolecules within the membrane, thus affecting the function of these molecules. Thus, when proteins encoded by the virus are located as individual and separate proteins within the membrane of infected cancer cells, the fluidity of the lipid bilayer allows independent movement of the molecules, which, for example, is suitable for biological function in a natural format. It may be of a similar, particularly suitable format.

In one embodiment, independently processed and expressed proteins are located (fixed) at different locations in the cancer cell membrane, such as physically separate locations.

In one embodiment, one or more proteins (eg, all proteins) encoded by the virus and expressed on the surface of the infected cancer cell are not fusion proteins.

As described above, in some embodiments, the protein is expressed as a fusion protein.

In one embodiment, the proteins of the present disclosure provide one or more distinct independent proteins for cell surface expression and one or more fusion proteins for cell surface expression.

Thus, in one embodiment, a protein according to the present disclosure comprises a DNA sequence encoding the plurality of proteins, eg, for expression on the surface or on infected cancer cells.

Thus, in one embodiment, a protein according to the present disclosure comprises two or more transgenes at the same or different positions in the viral genome. When located at the same location in the viral genome, multiple proteins will still be independently expressed on the surface of the cancer cell.

In one embodiment, multiple proteins (including fusion proteins) are encoded at different locations in the viral genome, eg at E3, and B _X and/or B _Y are separately expressed on the surface of infected cancer cells.

In one embodiment, a plurality of proteins (including fusion proteins) are encoded at the same location in the viral genome and expressed together on the surface of infected cancer cells, wherein, for example, the encoded protein is provided as a fusion protein, in particular wherein the fusion protein Includes B7 protein or an active fragment thereof.

In one embodiment, the B7 protein in the fusion protein is a full-length protein, particularly a protein described herein, such as B7-1 and/or B7-2, fused or linked to another protein of interest or an active fragment thereof. In one embodiment, the fusion protein is transmembrane from the B7 protein. In one embodiment, B7 is an active fragment excluding a transmembrane domain. In the latter embodiment, transmembrane other than those derived from the B7 protein can be used to ensure that the fusion protein is presented on the surface of the infected cancer cell.

In one embodiment, multiple proteins are encoded at the same location in the virus and are expressed together as one or more fusion proteins on the surface of infected cancer cells.

When the positions of the gene(s) encoding the protein or protein(s) of interest in the virus are identical, the genes can be linked, for example by an IRES sequence or a 2A peptide.

In one embodiment, a protein according to the present disclosure "encodes a polypeptide selected from the group comprising, for example, cytokines, chemokines, ligands, and antibody molecules, such as antagonistic antibody molecules, and agonistic antibody molecules. A second" transgene and optionally a third transgene (ie, one or more of the plurality of proteins).

In one embodiment, the additional protein or protein binds to CD3, CD28, CD80, CD86, 4-1BB, GITR, OX40, CD27, CD40 and combinations in a form suitable for expression on the surface of, for example, cancer cells. , Antibody fragments or protein ligands.

In one embodiment, the additional proteins are, for example, Muromonap-CD3 (also known as OKT3), otelixizumab (also known as TRX4), teplizumab (also known as hOKT3γ1 (Ala-Ala ), or an anti-CD3 antibody independently selected from visilizumab.

In one embodiment, the anti-CD3 antibody is part of a fusion protein in the form of an antibody fragment, e.g., a transmembrane region of another protein, e.g., a transmembrane domain from a PDGF receptor or from a cell surface form of IgG. scFv.

In one embodiment, the antibody molecule is a group comprising an inhibitor of angiogenesis factor, such as an anti-VEGF antibody molecule, and an inhibitor of T cell deactivation factor, such as an anti-CTLA-4, anti-PD1 or anti-PDL1 antibody molecule. It is an inhibitor independently selected from (antagonist antibody). In one embodiment, the antibody molecule is an agent independently selected from the group comprising antibodies against CD40, GITR, OX40, CD27 and 4-1BB.

In one embodiment, the additional transgene comprises IL-2, IFNα, IFNβ, IFNγ, GM-CSF, IL-15, IL-12 and fms-related tyrosine kinase 3 ligand (FLT3L). It encodes a cytokine selected from the group, or a soluble variant thereof. Advantageously, one or more of these groups of proteins expressed by viruses, particularly as free proteins secreted from cancer cells, may be particularly suitable for stimulating an immune response in vivo against cancer cells.

In one embodiment, the additional transgene encodes a chemokine selected from the group comprising MIP1-alpha, IL-8, CCL5, CCL17, CCL20, CCL22, CXCL9, CXCL10, CXCL11, CXCL13, CXCL12, CCL2, CCL19 and CCL21. . Advantageously, one or more of these groups of proteins are expressed by viruses, as free proteins that can be secreted from cancer cells may be particularly suitable for attracting immune cells and stimulating an immune response against cancer cells in vivo. .

In one embodiment, in addition to at least the B7 protein or active fragment thereof expressed on the surface of the infected cancer cell, one or more molecules are also expressed and/or secreted on the surface.

Thus, in one embodiment, the virus encodes B7-1, B7-2, or an active fragment of any one of them, or a combination thereof.

Thus, in one embodiment, the virus is B7-1, B7-2 or an active fragment of any one of them or a combination thereof and, in particular, the protein as an individual protein on the cell surface for expression on the surface of the infected cancer cell. When expressed, it also encodes an anti-CD3 (agonist) antibody or antibody binding fragment (eg, scFv) for expression on the surface of cancer cells.

Thus, in one embodiment, the virus is B7-1, B7-2, or an active fragment of any one of them, or a combination thereof, for expression on the surface of infected cancer cells, and also for expression on the surface of cancer cells. Or encoding an anti-VEGF (antagonist) antibody or binding fragment thereof, for example for release from cancer cells by secretion or after lysis/killing of infected cancer cells.

Thus, in one embodiment, the virus is B7-1, B7-2, or an active fragment of any one of them, or a combination thereof, for expression on the surface of infected cancer cells, and also for expression on the surface of cancer cells. Or antibodies, antibody fragments that bind to CD3, CD28, CD80, CD86, 4-1BB, GITR, OX40, CD27, CD40, for example for release from cancer cells by secretion or after lysis/kill of infected cancer cells. Or encodes a protein ligand.

Thus, in one embodiment, the virus is B7-1, B7-2 or any one of the active fragments or a combination thereof for expression on the surface of infected cancer cells, and after cell lysis/kill of infected cancer cells. For example, cytokine selected from IL-2, IFN-alpha, IFN-beta, IFN-gamma, GM-CSF, IL-15, IL-12 and FLT3L, especially for release from cancer cells by secretion or release. Encrypt.

Thus, in one embodiment, the virus is B7-1, B7-2 or any one of the active fragments or a combination thereof for expression on the surface of infected cancer cells, and after cell lysis/kill of infected cancer cells. For example, chemokines selected from MIP1-alpha, IL-8, CCL5, CCL17, CCL20, CCL22, CXCL9, CXCL10, CXCL11, CXCL13, CXCL12, CCL2, CCL19, CCL21, especially for release from cancer cells by secretion or release. Is encrypted.

Thus, in one embodiment, the virus is B7-1, B7-2 or an active fragment of any one of them or a combination thereof, and, in particular, the protein is an individual protein on the surface of the infected cancer cell. Also encodes an anti-CD3 (agonist) antibody or antibody binding fragment (e.g., scFv) for expression on the surface of cancer cells, e.g., especially for release from cancer cells by secretion or infected After cell lysis/kill of cancer cells, IL-2, IFN-alpha, IFN-gamma, GM-CSF, IL-15, IL-12, FLT3L, MIP1-alpha, IL-8, CCL5, CCL17, CCL20, CCL22 , CXCL9, CXCL10, CXCL11, CXCL13, CXCL12, CCL2, CCL19, CCL21.

Thus, in one embodiment, the virus is B7-1, B7-2 or an active fragment of any one of them or a combination thereof, and, in particular, the protein is an individual protein on the surface of the infected cancer cell. When expressed as) also encodes an anti-CD3 (agonist) antibody or antibody fragment (e.g., scFv) for expression on the surface of cancer cells, and also for expression on the surface of cancer cells or, for example, of an infected cancer cell. Antibodies, antibody fragments that bind to CD28, CD80, CD86, 4-1BB, GITR, OX40, CD27, CD40 or anti-VEGF (antagonist) antibodies for release from cancer cells by secretion or release after lysis/killing or It further encodes a protein ligand.

Thus, in one embodiment, the virus is B7-1, B7-2, or an active fragment of any one of them, or a combination thereof, for expression on the surface of an infected cancer cell, and, for example, a cell of an infected cancer cell. For release from cancer cells by secretion after lysis/kill, IL-2, IFNα, IFNβ, IFNγ, GM-CSF, IL-15 and IL-12, FLT3L, MIP1α, IL-8, CCL5, CCL17, CCL20 , CCL22, CXCL9, CXCL10, CXCL11, CXCL13, CXCL12, CCL2, CCL19, CCL21.

Thus, in one embodiment, the virus is B7-1, B7-2 or an active fragment of any one of them or a combination thereof, and, in particular, the protein is an individual protein on the surface of the infected cancer cell. Also encodes an anti-CD3 (agonist) antibody or antibody-binding fragment (e.g. scFv) for expression on the surface of cancer cells, especially secreted before and after cell lysis/kill of infected cancer cells. Cytokines independently selected from IL-2, IFNα, IFNγ, GM-CSF, IL-15 and IL-12, and/or RANTES (CCL5), MIP1α (LD78α (CCL3), which can be released from cancer cells by Alternatively, a chemokine selected from LD78β (CCL3L1) isoform), MIP1β, is further encoded.

In one embodiment, particularly which can be combined with any of the above embodiments, the virus further encodes an anti-PD-1 antibody (antagonist).

In one embodiment, the protein or proteins encoded in the transgene cassette for cell membrane expression may also comprise a peptide linker or spacer between the transmembrane domain and the extracellular ligand binding domain. Such linkers or spacers can add flexibility to cell surface expressed proteins, e.g., on adjacent cells, increasing the ability of the protein to interact with its target molecule. Such linkers or spacers may also be designed or selected to promote dimerization or trimerization of proteins on the cell surface, through disulfide bond formation or protein-protein interaction. For example, the hinge region of an immunoglobulin molecule or CD8 can be used to enhance both flexibility and dimerization.

In one embodiment, the protein or proteins encoded in the transgene cassette may also comprise a peptide tag. Peptide tags may include c-myc, poly-histidine, V5 or FLAG tags and may be located at the N-terminus or C-terminus of an intracellular or extracellular polypeptide, for example in a protein or in an extracellular loop. It can be encoded between the transmembrane domain and the extracellular domain. Peptide tags can be used as spacers or linkers between different protein domains, such as transmembrane and extracellular domains, and can be used for detection or purification, or for detection of proteins or cells expressing the protein.

In one embodiment, one or more additional transgenes (other than the gene encoding the B7 protein or fragment thereof) are under the control of an exogenous or endogenous promoter, eg, an endogenous promoter. In one embodiment, the transgene in the E3 region (B ₂ ) is under the control of an exogenous promoter.

In one embodiment, the one or more additional transgene genes are located between the fiber L5 and E3 regions in the adenovirus genome, e.g., at the B _X position in the construct of formula (I), particularly under the control of an exogenous promoter. Thus, in one embodiment _{, the transgene at B X} is under the control of an exogenous promoter.

In one embodiment, the one or more additional transgene genes are between the fiber L5 and E4 regions in the adenovirus genome, for example the construction of formula ( I ) or ( Ia ), particularly under the control of an endogenous promoter, such as a major late promoter. It is in the B _Y position on the offering. It may be other than the B7 protein encoded in region B _{Y or an active fragment thereof.}

In one embodiment, there is provided a composition comprising a tumor cell disrupting adenoprotein according to the present disclosure, for example a pharmaceutical composition comprising a particularly pharmaceutically acceptable excipient, such as a diluent or carrier.

In one embodiment, there is provided a tumor cell disrupting adenoprotein or a composition comprising the same according to the present disclosure for use in therapy, particularly for use in the treatment of cancer.

In one embodiment, a method of treating a patient in need thereof is provided comprising administering a therapeutically effective amount of a tumor cell disruption protein according to the present disclosure or a composition comprising the same, such as a pharmaceutical composition.

In one embodiment, a tumor according to the present disclosure for the manufacture of a medicament for the treatment of cancer, in particular carcinoma, e.g. colorectal cancer, lung cancer, bladder cancer, kidney cancer, pancreatic cancer, liver cancer, head and neck cancer, breast or ovarian cancer. The use of a cell-degrading adenoprotein or a composition comprising the same is provided.

In one embodiment, at least 50% of the protein according to the present disclosure (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) of the genomic sequence, and the B7 protein or active fragment thereof, for example the B7 protein disclosed herein, such as B7 A polynucleotide comprising a sequence encoding -1 or an active fragment thereof is provided. In one embodiment, the polynucleotide sequence is in the form of a plasmid.

In one embodiment, a host cell, such as a mammalian cell, such as a HEK293 cell or a derivative thereof, is provided comprising a tumor cell disruption protein according to the present disclosure or a polynucleotide sequence according to the present disclosure.

In one embodiment, there is provided a method of preparing a tumor cell disruption adenoprotein according to the present disclosure, comprising the step of inserting a polynucleotide encoding a B7 protein or an active fragment thereof into a tumor cell disruption adenovirus.

In one embodiment, a method of replicating a protein according to the present disclosure is provided comprising culturing the host cell in the presence of a virus under conditions suitable for replication. In general, the method will comprise an additional step of harvesting the virus, for example from the supernatant or after lysis of the host cell.

Justice

Tumor cell disruption virus having selectivity for cancer cells, as used herein, refers to a virus that preferentially kills cancer cells, for example because it preferentially infects cancer cells and/or viruses This is because the life cycle depends on genes such as p53 that are dysregulated in cancer cells, for example overexpressed. In one embodiment, the tumor cell disruption virus preferentially infects cancer cells and, for example, according to EnAd, is passed on to replicate its genome to produce new viral particles and to produce the capsid protein.

Selectivity (therapeutic index) for cancer cells can be tested as described in WO2005/118825, incorporated herein by reference.

A transgene, as used herein, refers to a gene inserted into the genomic sequence of an adenovirus, and the gene is non-natural (exogenous) to the virus, or is usually not found at that specific location in the virus. Examples of transgenes are provided herein. Transgenes, as used herein, also include functional fragments of genes that are part of a gene, suitable to perform most of the function or functions of a full-length gene, e.g., 50% or more of the functions, when inserted. do.

Transgenes and coding sequences are used interchangeably herein, in the context of inserts into the viral genome, unless the context indicates otherwise. A coding sequence, as used herein, refers to a DNA sequence that encodes, for example, a functional RNA, peptide, polypeptide or protein. Typically, the coding sequence is a cDNA for a transgene encoding a functional RNA, peptide, polypeptide or protein of interest. Functional RNAs, peptides, polypeptides and proteins of interest are described below.

In one embodiment, a transgene, as used herein, refers to a segment of DNA containing a gene or cDNA sequence isolated from one organism and introduced into a different organism, i.e., a protein of the present disclosure. In one embodiment, this non-native segment of DNA will generally retain the ability to produce a functional RNA, peptide, polypeptide or protein. The transgene used may for example encode a single protein or an active fragment thereof, a chimeric protein or a fusion protein.

Clearly, the viral genome contains the coding sequence of DNA. The endogenous (naturally occurring gene) in the genomic sequence of a virus is not considered a transgene unless, within the context of the present specification, it is at a non-natural location or is subsequently modified by recombinant techniques such that it is in a non-natural environment.

Thus, in one embodiment, the inserted transgene encodes a human or humanized protein, polypeptide or peptide.

In one embodiment, the transgene comprises a DNA sequence encoding a B7 protein or an active fragment thereof. The present disclosure provides that the B7 protein or activated fragment thereof can be provided in one or more formats independently selected from a fusion protein, a simple B7 protein or an active fragment thereof.

A simple B7 protein or active fragment thereof, as used herein, is essentially a wild-type protein, for example not part of a fusion protein, and having the same or similar sequence as a related known protein, particularly a known human protein. , Means protein. Simple genes also include those in which 10% of the amino acids have been substituted or deleted over the entire length of the relevant protein.

GPI anchor, as used herein, refers to a glycolipid that can be attached to the C-terminus of a protein during post-translational modification. It consists of a phosphatidylinositol group linked through a carbohydrate-containing linker (glucosamine and mannose glycosided to the inositol residue) and through an ethanolamine phosphate (EtNP) bridge to the C-terminal amino acid of the mature protein. The two fatty acids in the hydrophobic phosphatidyl-inositol group anchor the protein to the cell membrane.

Glypiated (GPI linked) proteins generally contain a signal peptide, directing it to the endoplasmic reticulum (ER). The C-terminus consists of a hydrophobic amino acid that remains inserted into the ER membrane. The hydrophobic end is then cleaved and replaced by a GPI-anchor. As the protein proceeds through the secretory pathway, it is transported through the vesicle to the Golgi apparatus and finally to the extracellular space where it remains attached to the outer plate of the cell membrane. Since glipiating is the only means of attaching these proteins to the membrane, cleavage of the group by phospholipase will result in controlled release of the protein from the membrane. The latter mechanism is used in vitro; That is, the membrane protein released from the membrane in the enzyme assay is a glipiated protein.

Phospholipase C (PLC) is an enzyme known to cleave phospho-glycerol bonds found in GPI immobilized proteins. Treatment by PLC will result in the release of GPI linked proteins from the outer cell membrane. Both the T cell markers Thy-1 and acetylcholinesterase, and intestinal and placental alkaline phosphatase are known to be GPI linked and are released by treatment with PLC. The GPI-linked protein is thought to be preferentially located on the lipid raft, suggesting a high level of systematization within the plasma membrane microdomain.

A review of GPI anchors written by Ferguson, Kinoshita and Hart is available in Chapter 11 of Essentials of Glycobiology 2 ^nd Edition.

virus

Replicable, in the context of the present specification, refers to a virus that possesses all possible machinery that replicates in cells in vitro and in vivo, ie replicates without the aid of a packaging cell line. Viral vectors that are capable of replicating in a complementary packaging cell line, for example deleted at least in the E1A region, are not replicable viruses in this context.

Viral vectors are replication defective viruses that require packaging cell lines (including transgenes) to replicate.

Replicable virus, as used herein, refers to a replicable virus or a virus whose replication is dependent on a factor in cancer cells, for example an upregulated factor, such as p53 or the like.

In one embodiment, the adenovirus is a human adenovirus. “Adenovirus”, “serotype” or adenovirus serotype, as used herein, can be assigned to any of more than 50 currently known adenovirus serotypes, classified as AF subgroups. , Means any adenovirus, and is further extended to any, yet, unidentified or unclassified adenovirus serotype, eg Strauss, “Adenovirus infections in humans,” as described in Table 1. in The Adenovirus, Ginsberg, ea., Plenum Press, New York, NY, pp. 451-596 (1984) and Shenk, "Adenoviridae: The Viruses and Their Replication," in Fields Virology, Vol. 2, Fourth Edition, Knipe. , 35ea., Lippincott Williams & Wilkins, pp. 2265-2267 (2001).

Adenoviruses are grouped based on their capsid.

In one embodiment, the adenovirus comprises or is independent from the group consisting of, for example, Ad3, Ad7, Ad11, Ad14, Ad16, Ad21, Ad34 and Ad51, such as Ad11, especially Ad11p (Slobitski strain). Is the B subgroup selected as. In one embodiment, the adenovirus of the invention has a capsid of subgroup B adenovirus, such as hexon and/or fibers, such as Ad11, especially Ad11p. In one embodiment, the adenovirus is Ad11 or has fibers of Ad11 and/or hexon and/or Fenton, such as Ad11p.

In one embodiment, the protein of the present disclosure is not a group A virus.

In one embodiment, the virus of the present disclosure does not include adeno death protein (ADP).

In one embodiment, the protein of the present disclosure is not a Group C virus.

In one embodiment, the protein of the present disclosure does not comprise a fragment of a portion of the Ad5 virus.

Enadenotuxireb (EnAd) is a chimeric tumor cell disruption adenovirus, formerly known as ColoAd1 (WO2005/118825), with fibers from Ad11p, Fenton and Hexon, and therefore it is a B subgroup virus. It has a chimeric E2B region containing DNA from Ad11p and Ad3. Almost all of the E3 region and part of the E4 region are deleted in EnAd. Thus, it has significant space in the genome to accommodate additional genetic material while remaining viable. Moreover, since EnAd is a B subgroup adenovirus, existing immunity in humans is less common than for example Ad5. Other examples of chimeric tumor cell disruption viruses with Ad11 fibers, Fenton and Hexon include OvAd1 and OvAd2 (see WO2006/060314).

EnAd appears to preferentially infect tumor cells, in which it replicates rapidly and causes cell lysis. This in turn creates an inflammatory immune response that can stimulate the body to fight cancer as well. It is assumed that part of the success of EnAd is related to the rapid replication of the virus in vivo.

Importantly, it has been clinically demonstrated that EnAd can be administered systemically (eg, by intravenous or intraperitoneal injection or infusion) and subsequently selectively infect and express proteins in tumor cells. EnAd, which can be shared by Ad11p, and other group B adenoviruses, especially those expressing the capsid protein of Ad11p (e.g., those described herein), are characterized by the fact that they do not directly inject the transgene into the tumor. , Makes it possible to express proteins on the surface of cancer cells, which is not feasible for many cancers.

EnAd selectively lyses tumor cells, but by arming them with transgenes, such as transgenes encoding cell signaling proteins or antibodies, or transgenes encoding aggregates that stimulate cell signaling protein(s), viruses Additional advantageous properties can be introduced, such as increasing the therapeutic activity of the virus or reducing the side effects of the virus.

Advantageously, arming the virus is by DNA encoding a given protein that can be expressed inside the cancer cell, for example by making the cell more visible to the immune system or preferentially to the target tumor cell, the therapeutic gene/ By delivering proteins, the body's own defenses can be used to fight tumor cells more effectively.

In one embodiment, the tumor cell disrupting adenoproteins of the present disclosure stimulate the immune system of a patient fighting tumors, for example by reducing the cancer's ability to suppress an immune response.

In one embodiment, the tumor cell disruption virus is a fiber from the same serotype, hexon and Fenton proteins, such as Ad11, especially Ad11p (e.g., 30812-31789, 18254-21100 and 13682 of the latter genomic sequence. -15367), and the nucleotide position is for Genbank number 217307399 (accession number: GC689208).

In one embodiment, the adenovirus is Enadenotuxireb (also known as EnAd and formerly ColoAd1). Enadenotuxireb, as used herein, refers to the chimeric adenovirus of SEQ ID NO: 21. It is a replicable tumor cell disruption chimeric adenovirus with enhanced therapeutic properties compared to wild-type adenovirus (see WO2005/118825). EnAd has a deletion in E3/E4 and a chimeric E2B region that characterizes DNA from Ad11p and Ad3. The structural change of enadenotouxireb results in a genome that is approximately 3.5 kb smaller than Ad11p, providing additional "space" for the insertion of the transgene.

The antibody molecule used is a complete antibody molecule having a full-length heavy and light chain, a bispecific antibody format comprising a full-length antibody or a fragment of any one of them, such as Fab, modified Fab, Fab', modified Fab', F (ab')2, Fv, single domain antibodies (e.g., VH or VL or VHH), scFv, divalent, trivalent or tetravalent antibodies, bis-scFv, diabodies, triabodies, tetrabodies and optional Of the above epitope binding fragments of, but not limited to (e.g., Holliger and Hudson, 2005, Nature Biotech. 23(9):1126-1136; Adair and Lawson, 2005, Drug Design Reviews-Online 2(3), 209-217). Methods for generating and preparing antibody fragments are well known in the art (see, eg, Verma et al., 1998, Journal of Immunological Methods, 216, 165-181). Other antibody fragments for use in the present invention include the Fab and Fab' fragments described in international patent applications WO2005/003169, WO2005/003170 and WO2005/003171. Multivalent antibodies may comprise multispecificity, eg bispecificity, or may be monospecific (see, eg, WO 92/22853, WO05/113605, WO2009/040562 and WO2010/035012).

Antibody, as used herein, unless the context indicates otherwise, refers to a full-length antibody.

Antibody binding fragments are fragments comprising a binding domain, such as VH and/or VL, which retain specificity for the target antigen to which it binds and, for example, Fab, modified Fab, Fab', modified Fab', F(ab' ) 2, Fv, single domain antibodies (e.g., VH or VL or VHH), scFv, divalent, trivalent or tetravalent antibodies, bis-scFv, diabodies, triabodies, tetrabodies and any of these Refers to an epitope binding fragment.

Linker

Linkers suitable for use in the fusion proteins of the present disclosure include:

Examples of hard linkers include the peptide sequences GAPAPAAPAPA (SEQ ID NO: 75), PPPP (SEQ ID NO: 76) and PPP.

Other linkers are listed in Table 4:

Formulas (I) and ( Ia ) Of the definition

Binding refers to a covalent bond that connects one DNA sequence to another DNA sequence, e.g., one section of the viral genome to another. Thus, when the variables in formulas (I ) and ( Ia ) represent a bond herein, the feature or element indicated by the bond is absent, i.e., deleted.

Since the structures of adenoviruses are generally similar, the following genetic elements are described in terms of structural genetic elements known to the skilled person and commonly used nomenclature to refer to them. When a genetic element is referred to herein, the present inventors mean a DNA sequence encoding the genetic element in an adenovirus or a DNA sequence encoding the same structural protein of the genetic element. The latter is related due to the duplication of the DNA code. The virus's preference for codon usage may need to be considered for optimized results.

Any structural genetic element from adenovirus used in the proteins of the present disclosure may comprise or consist of a native sequence, or at least 95%, such as 96%, 97%, 98%, 99% or 100% Can have similarity to the length of. The original sequence can be modified to omit 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% of the genetic material. The skilled person knows that when making changes, the reading frame from the virus must not be destroyed so that the expression of the structural protein is destroyed.

In one embodiment, the predetermined genetic element is a full-length sequence, ie, a full-length gene. Full-length gene, as used herein, refers to at least the entirety of the coding sequence of a gene, but may include any associated noncoding region, especially if it is related to the function of the gene.

In one embodiment, a given genetic element is less than the full length and retains the same or corresponding function as the full length sequence.

In one embodiment, for any given genetic element in the constructs of the present disclosure, the DNA sequence can be less than the full length, has no functionality, e.g., the E3 region can be wholly or partially deleted. However, since the E3 region optimizes the space available to insert the transgene, it may be useful to delete essentially all of the E3 regions.

Structural genes encoding structural or functional proteins of adenovirus are generally linked by non-coding regions of DNA. Thus, there is some flexibility as to whether to "cut" the genomic sequence of the structural genetic element of interest (especially its non-coding region) for the purpose of inserting the transgene into the protein of the present disclosure. Thus, for the purposes of this specification, a genetic element will be considered a structural genetic element of the reference to the extent that it is suitable for the purpose and does not encode an exogenous material. Thus, where appropriate, the gene will be associated with a suitable non-coding region, for example as found in the natural structure of a virus.

Thus, in one embodiment, an insert, such as DNA encoding a restriction site and/or a transgene, is inserted into a non-coding region of genomic viral DNA, such as an intron or intergenic sequence. Even so, some non-coding regions of adenovirus may have a function, for example in alternating splicing, transcriptional regulation or translational regulation, and these may need to be considered.

The sites identified herein, associated with the L5 region, are suitable for receiving a variety of DNA sequences encoding complex aggregates, such as RNAi, cytokines, single-chain or multimeric proteins, such as antibodies.

Gene, as used herein, refers to a coding sequence and any non-coding sequence associated therewith, such as introns and associated exons. In one embodiment, the gene comprises or consists of only essential structural components, e.g., the coding region.

The discussion on the specific structural genetic elements of adenovirus is as follows.

The Inverted Terminal Repeat (ITR) sequence is common to all known adenoviruses (so named because of its symmetry) and is the origin of viral chromosomal replication. Another characteristic of its sequence is its ability to form hairpins.

5'ITR, as used herein, refers to some or all of the ITR from the 5 end of the adenovirus that retains the function of the ITR when incorporated into the adenovirus at the appropriate position. In one embodiment, the 5′ITR is a sequence from about 1 bp to 138 bp of SEQ ID NO: 21 or a sequence that is 90%, 95%, 96%, 97%, 98% or 99% identical thereto, particularly SEQ ID NO: 21 It comprises or consists of a sequence consisting of about 1bp to 138bp of.

3'ITR, as used herein, refers to some or all of the ITR from the 3'end of the adenovirus that retains the function of the ITR when incorporated into the adenovirus at the appropriate position. In one embodiment, the 3'ITR is a sequence from about 32189 bp to 32326 bp of SEQ ID NO: 21 or a sequence that is 90%, 95%, 96%, 97%, 98% or 99% identical thereto depending on the total length, particularly SEQ ID NO: 21 It comprises or consists of a sequence consisting of about 32189bp to 32326bp of.

B1, as used herein, is a DNA sequence encoding part or all of E1A from adenovirus, part or all of E1B region of adenovirus, and independently part or all of E1A and E1B regions of adenovirus Means.

When B1 is bound, the E1A and E1B sequences will be omitted from the virus. In one embodiment, B1 is a binding and thus the virus is a vector.

In one embodiment, B1 further comprises a transgene. Deletion so that the E1 region can accommodate a transgene that can be inserted in a destructive manner into the E1 region (ie, in the "middle" of the sequence), or that some or all of the E1 region provides more room to accommodate the genetic material. It is known in the art that it can be.

E1A, as used herein, refers to a DNA sequence encoding part or all of the adenovirus E1A region. Here, the latter means polypeptide/protein E1A. The protein encoded by the E1A gene has the same function as the wild-type (ie, the corresponding non-mutated protein); Has increased function compared to wild-type protein; Conservative or non-conservative amino acid changes (e.g., full-length) to have a reduced pig function compared to a wild-type protein, such as no function, or to have a new function compared to a wild-type protein or a combination thereof, as appropriate. To have 1, 2, 3, 4 or 5 amino acid changes, additions and/or deletions) across, it can be mutated.

E1B, as used herein, refers to a DNA sequence encoding part or all of the adenovirus E1B region (i.e., polypeptide or protein), and the protein encoded by the E1B gene/region is wild-type (corresponding The same function as the non-mutated protein); Has increased function compared to wild-type protein; Conservative or non-conservative amino acid changes (e.g., full-length) to have a reduced pig function compared to a wild-type protein, such as no function, or to have a new function compared to a wild-type protein or a combination thereof, as appropriate. To have 1, 2, 3, 4 or 5 amino acid changes, additions and/or deletions) across, it can be mutated.

Thus, B1 can be modified or unmodified for a wild-type E1 region, such as wild-type E1A and/or E1B. The skilled person can readily ascertain whether E1A and/or E1B is present, (partially) deleted or mutated.

Wild type, as used herein, refers to a sequence from a known adenovirus or a known adenovirus. Known adenoviruses are identified and named regardless of whether sequence information is available.

In one embodiment, B1 has the sequence of 139 bp to 3932 bp of SEQ ID NO: 21.

B _A , as used herein, encodes an E2B-L1-L2-L3-E2A-L4 region comprising any non-coding sequence, as appropriate (especially corresponding to the native sequence from adenovirus). Refers to the DNA sequence. In general, this sequence will not contain a transgene. In one embodiment, the sequence is a contiguous sequence from a known adenovirus, e.g., a serotype described in Table 1, in particular a group B virus, e.g. Ad3, Ad7, Ad11, Ad14, Ad16, Ad21, Ad34, Ad35, Substantially similar or identical to Ad51 or a combination thereof, such as Ad3, Ad11, or combinations thereof. In one embodiment, E2B-L1-L2-L3-E2A-L4 is meant to include these genetic elements and other structural genetic elements associated with the region, e.g. BA encodes protein IV2a, e.g. It will generally contain a sequence of: IV2A IV2a-E2B-L1-L2-L3-E2A-L4.

In one embodiment, the E2B region is chimeric. That is, it contains DNA sequences from two or more different adenovirus serotypes, such as Ad3 and Ad11, such as Ad11p. In one embodiment, the E2B region has a sequence of 5068 bp to 10355 bp of SEQ ID NO: 21 or a sequence that is 95%, 96%, 97%, 98% or 99% identical to it over the entire length.

In one embodiment, _{E2B in component B A} comprises the sequence set forth in SEQ ID NO: 22 (corresponding to SEQ ID NO: 3 disclosed in WO2005/118825).

In one embodiment, B _A has the sequence of 3933 bp to 27184 bp of SEQ ID NO: 21.

E3, as used herein, refers to a DNA sequence encoding part or all of the adenovirus E3 region (i.e., protein/polypeptide), and the protein encoded by the E3 gene is wild-type (corresponding non-mutant Protein) and the same function; Has increased function compared to wild-type protein; Conservative or non-conservative amino acid changes (e.g., one , 2, 3, 4 or 5 amino acid changes, additions and/or deletions).

In one embodiment, the E3 region is an adenovirus serotype provided in Table 1 or a combination thereof, particularly a group B serotype, such as Ad3, Ad7, Ad11 (particularly Ad11p), Ad14, Ad16, Ad21, Ad34, Ad35, Ad51 or a combination thereof, such as Ad3, Ad11 (particularly Ad11p) or a combination thereof. In one embodiment, the E3 region has the sequence set forth in SEQ ID NO: 23.

In one embodiment, the E3 region is partially deleted, e.g. 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40 %, 35%, 30%, 25%, 20%, 15%, 10%, 5% are deleted.

In one embodiment B ₂ is binding and the DNA encoding the E3 region is absent.

In one embodiment, the DNA encoding the E3 region can be replaced or interrupted by a transgene. The E3 region replaced by a transgene, as used herein, as used herein, includes some or all of the E3 region replaced by a transgene.

In one embodiment, the B ₂ region comprises the sequence of 27185 bp to 28165 bp of SEQ ID NO: 24.

In one embodiment B ₂ consists of the sequence of 27185 bp to 28165 bp of SEQ ID NO: 24.

B _X , as used herein, refers to a DNA sequence close to the 5'end of the L5 gene of _{B B.} Near or proximal to the 5'end of the L5 gene, as used herein, is adjacent (proximate) to the 5'end of the L5 gene or the noncoding region originally associated therewith, i.e., the 5'prime end of the L5 gene or it It means that it is in contact with or adjacent to the non-encrypted area originally associated with Alternatively, near or proximal can mean close to the L5 gene, such that there is no coding sequence between the _{5'end of the L5 gene and the B X region.}

Thus, in one embodiment B _X is linked directly to the base of L5, which, for example, indicates the beginning of the coding sequence of the L5 gene.

Thus, in one embodiment B _X is directly linked to the base of L5 (which, for example, indicates the beginning of the noncoding sequence), or directly linked to the noncoding region that is naturally linked to L5. The noncoding region naturally associated with L5, as used herein, refers to a part of the entire noncoding region, which is part of or adjacent to the L5 gene, but not part of another gene.

In one embodiment, B _X comprises the sequence of SEQ ID NO: 24. This sequence is an artificial non-coding sequence, wherein a DNA sequence comprising, for example, a transgene (or transgene cassette), a restriction site or a combination thereof, can be inserted therein. This sequence is advantageous because it acts as a buffer in that it allows some flexibility for the exact location of the transgene, while minimizing the destructive effect on viral stability and viability.

The insert(s) may be at the 5'end, anywhere within SEQ ID NO: 24 from the 3'end or at any point from bp 1 to 201, for example base pairs 1/2, 2/3, 3/4, 4/5 , 5/6, 6/7, 7/8, 8/9, 9/10, 10/11, 11/12, 12/13, 13/14, 14/15, 15/16, 16/17, 17 /18, 18/19, 19/20, 20/21, 21/22, 22/23, 23/24, 24/25, 25/26, 26/27, 27/28, 28/29, 29/30 , 30/31, 31/32, 32/33, 33/34, 34/35, 35/36, 36/37, 37/38, 38/39, 39/40, 40/41, 41/42, 42 /43, 43/44, 44/45, 45/46, 46/47, 47/48, 48/49, 49/50, 50/51, 51/52, 52/53, 53/54, 54/55 , 55/56, 56/57, 57/58, 58/59, 59/60, 60/61, 61/62, 62/63, 63/64, 64/65, 65/66, 66/67, 67 /68, 68/69, 69/70, 70/71, 71/72, 72/73, 73/74, 74/75, 75/76, 76/77, 77/78, 78/79, 79/80 , 80/81, 81/82, 82/83, 83/84, 84/85, 85/86, 86/87, 87/88, 88/89, 89/90, 90/91, 91/92, 92 /93, 93/94, 94/95, 95/96, 96/97, 97/98, 98/99, 99/100, 100/101, 101/102, 102/103, 103/104, 104/105 , 105/106, 106/107, 107/108, 108/109, 109/110, 110/111, 111/112, 112/113, 113/114, 114/115, 115/116, 116/117, 117 /118, 118/119, 119/120, 120/121, 121/122, 122/123, 123/124, 124/125, 125/126, 126/127, 12 7/128, 128/129, 129/130, 130/131, 131/132, 132/133, 133/134, 134/135, 135/136, 136/137, 137/138, 138/139, 139/ 140, 140/141, 141/142, 142/143, 143/144, 144/145, 145/146, 146/147, 147/148, 148/149, 150/151, 151/152, 152/153, 153/154, 154/155, 155/156, 156/157, 157/158, 158/159, 159/160, 160/161, 161/162, 162/163, 163/164, 164/165, 165/ 166, 166/167, 167/168, 168/169, 169/170, 170/171, 171/172, 172/173, 173/174, 174/175, 175/176, 176/177, 177/178, 178/179, 179/180, 180/181, 181/182, 182/183, 183/184, 184/185, 185/186, 186/187, 187/188, 189/190, 190/191, 191/ It can occur within 192, 192/193, 193/194, 194/195, 195/196, 196/197, 197/198, 198/199, 199/200 or 200/201.

In one embodiment, B _X comprises SEQ ID NO: 24 having a DNA sequence inserted between bp 27 and bp 28, or corresponding sites between positions 28192 bp and 28193 bp of SEQ ID NO: 24.

In one embodiment, B _X has the sequence of 28166 bp to 28366 bp of SEQ ID NO: 21. In one embodiment, B _X is a bond.

B _B , as used herein, refers to a DNA sequence encoding the L5 region. As used herein, the L5 region, as appropriate in the context, refers to a DNA sequence containing a gene encoding a fibrous polypeptide/protein. The fiber gene/region encodes a fiber protein, the main capsid component of adenovirus. Fibers act in receptor recognition and contribute to the ability of adenoviruses to selectively bind and infect cells.

In the proteins of the present disclosure, the fibers can be derived from any adenovirus serotype and chimeric adenovirus, as the results of changing the fibers for one of the different serotypes are also contemplated by the present disclosure. In one embodiment, the fiber is from a group B virus, particularly Ad11, such as Ad11p.

In one embodiment, B _B has the sequence of 28367 bp to 29344 bp of SEQ ID NO: 21.

With respect to B _Y , a DNA sequence, as used herein, refers to a DNA sequence proximate the 3'end of the L5 gene of _{B B.} Near or proximal to the 3'end of the L5 gene, as used herein, is adjacent (proximate) to the 3'end of the L5 gene or the noncoding region originally associated therewith, i.e., the 3'prime end of the L5 gene or it It means that the non-coding region originally associated with (ie, all or part of the non-coding sequence endogenous to L5) is contiguous or contiguous. Alternatively, near or proximal can mean close to the L5 gene, such that there is no coding sequence between the _{3'end of the L5 gene and the B Y region.}

Thus, in one embodiment, B _Y is directly linked to the base of L5, which represents the “end” of the coding sequence.

Thus, in one embodiment, B _Y is linked directly to the base of L5 (which represents the “end” of the noncoding sequence), or directly linked to the noncoding region naturally associated with L5.

Originally and naturally, they are used interchangeably herein. In one embodiment, B _Y comprises the sequence of SEQ ID NO: 25. This sequence is a non-coding sequence into which, for example, a DNA sequence comprising a transgene (or transgene cassette), a restriction site or a combination thereof can be inserted. This sequence is advantageous because it acts as a buffer in that it allows some flexibility for the exact location of the transgene, while minimizing the destructive effect on viral stability and viability.

The insert(s) is at the 5'end, anywhere within SEQ ID NO: 22 from the 3'end, or at any point between bp 1 to 35, for example base pairs 1/2, 2/3, 3/4, 4 /5, 5/6, 6/7, 7/8, 8/9, 9/10, 10/11, 11/12, 12/13, 13/14, 14/15, 15/16, 16/17 , 17/18, 18/19, 19/20, 20/21, 21/22, 22/23, 23/24, 24/25, 25/26, 26/27, 27/28, 28/29, 29 May occur between /30, 30/31, 31/32, 32/33, 33/34, or 34/35.

In one embodiment, B _Y comprises SEQ ID NO: 25 having a DNA sequence inserted between positions 12 and 13 or corresponding to 29356 bp and 29357 bp in SEQ ID NO: 21. In one embodiment, the insert is a restriction site insert. In one embodiment, the restriction site insert comprises one or two restriction sites. In one embodiment, the restriction site is a 19 bp restriction site insert comprising two restriction sites. In one embodiment, the restriction site insert is a 9 bp restriction site insert comprising one restriction site. In one embodiment, the restriction site insert comprises 1 or 2 restriction sites and at least 1 transgene, such as 1 or 2 or 3 transgenes, such as 1 or 2 transgenes. In one embodiment, the restriction site is a 19 bp restriction site insert comprising two restriction sites and at least one transgene, such as one or two transgenes. In one embodiment, the restriction site insert is a 9 bp restriction site insert comprising one restriction site and at least one transgene, such as one or two transgenes. In one embodiment, the two restriction sites sandwich one or more, such as two transgenes (eg, in a transgene cassette). In one embodiment, when B _Y comprises two restriction sites, the restriction sites are different from each other. In one embodiment _{, the one or more restriction sites in B Y} are non-naturally occurring (eg, unique) in the particular adenovirus genome into which it has been inserted. In one embodiment _{, the one or more restriction sites in B Y} are different from other restriction sites located somewhere in the adenovirus genome, e.g., a naturally occurring restriction site or a restriction site introduced into another part of the genome such as _{B X.} It is different from Thus, in one embodiment, the restriction site or sites allow the DNA in the fragment to be specifically cleaved.

In one embodiment, B _Y has the sequence of 29345 bp to 29379 bp of SEQ ID NO: 21. In one embodiment, B _Y is a bond.

In one embodiment, the insert is after bp 12 in SEQ ID NO: 25.

In one embodiment, the insert is at position about 29356 bp of SEQ ID NO: 21.

In one embodiment, the insert is a transgene cassette comprising one or more, such as 1, 2 or 3, such as 1 or 2 transgenes.

E4, as used herein, refers to a DNA sequence encoding part or all of the adenovirus E4 region (i.e., polypeptide/protein region), and the protein encoded by the E4 gene is conserved or non-conserved. Have an appropriate amino acid change (eg, 1, 2, 3, 4 or 5 amino acid changes, additions and/or deletions) and the same function as wild type (corresponding non-mutated protein); Has increased function compared to wild-type protein; It can be mutated to have a reduced pig function compared to a wild-type protein, such as no function, or, as appropriate, a new function compared to a wild-type protein or a combination thereof.

In one embodiment, the E4 region is partially deleted, e.g. 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40 %, 35%, 30%, 25%, 20%, 15%, 10% or 5% are deleted. In one embodiment, the E4 region has a sequence of 32188 bp to 29380 bp of SEQ ID NO: 21.

In one embodiment E4 is present except for the deleted E4orf4 region.

In one embodiment, B ₃ is a bond, ie where E4 is absent.

In one embodiment, B ₃ has the sequence consisting of 32188 bp to 29380 bp of SEQ ID NO: 21.

As used herein, numerical ranges are inclusive of the end points.

Those skilled in the art will understand that in the present specification, genetic elements of formulas, such as formulas ( I ), ( Ia ), are contiguous and can implement non-coding DNA sequences, and genes and coding DNA sequences (structural features) referred to herein. will be. In one or more embodiments, the formulas of the present disclosure attempt to describe naturally occurring sequences in the adenovirus genome. In this context, it will be clear to the skilled person that the formula refers to the major genetic elements that characterize the relevant sections of the genome, and is not intended to be a thorough description of the genomic stretch of DNA.

E1A, E1B, E3 and E4, as used herein, are each independently a wild-type and equivalent, mutated or partially deleted form of each region as described herein, particularly known adenoviruses. Means the wild-type sequence from.

"Insert", as used herein, refers to a DNA sequence incorporated at the 5'end, 3'end, or within a given DNA sequence reference segment to interrupt the reference sequence. The reference sequence is used as the reference point where the insert is located. Inserts in the context of this disclosure generally occur within SEQ ID NO: 24 or SEQ ID NO: 25. The insert can be a restriction site insert, a transgene cassette, or both. When the sequence is interrupted, the virus still contains the original sequence, but generally it will be in two fragments sandwiching the insert.

In one embodiment, the transgene or transgene cassette does not contain an unbiased insertion transgene, such as the TN7 transgene or portions thereof. Tn7 transfer factor, as used herein, refers to an unbiased insertion transfer factor as described in WO2008/080003.

In one embodiment, the transgene or transgene cassette further comprises a regulatory element or sequence.

Other regulatory sequences

A “regulator of gene expression” (or regulator/regulatory element), as used herein, is a genetic element, such as a promoter, enhancer, that plays a role in gene expression, usually by initiating or enhancing transcription or translation. Or it means a splice acceptor sequence.

“Splice acceptor sequence”, “splice acceptor” or “splice site”, as used herein, when recognized by the small nuclear ribonucleoprotein of the spliceosome complex It means the control sequence that determines the. Once assembled, spliceosomes allow splicing between the splice acceptor sites of the mRNA molecule to the upstream splice donor sites producing mature mRNA molecules, which can be translated to produce a single polypeptide or protein. Catalyzes.

Splice acceptor sequences of different sizes can be used in the present invention, which can be described as short splice acceptors (small), splice acceptors (medium) and branched splice acceptors (high).

SSA, as used herein, typically refers to a short splice acceptor, comprising a splice site, for example 4 bp. SA, as used herein, refers to a splice acceptor, typically comprising a short splice acceptor and a polypyrimidine track, for example 16 bp. bSA, as used herein, refers to a branched splice acceptor, typically comprising short splice acceptors, polypyrimidine tracks and branch points, for example 26 bp.

In one embodiment, the splice acceptor used in the constructs of the present disclosure is CAGG or SEQ ID NO: 3 or 4. In one embodiment, the SSA has the nucleotide sequence of SEQ ID NO: CAGG. In one embodiment, the SA has the nucleotide sequence of SEQ ID NO: 23. In one embodiment, the bSA has the nucleotide sequence of cagg. In one embodiment, the splice acceptor sequence is independently selected from the group comprising tgctaatctt cctttctctc ttcagg (SEQ ID NO: 4), tttctctctt cagg (SEQ ID NO: 3) and cagg.

In one embodiment, the splice site is immediately preceded by a consensus Kozak sequence comprising CCACC (i.e., followed in a 5'to 3'direction). In one embodiment, the splice site and Kozak sequence are located (separated) up to 100 bp. In one embodiment, the Kozak sequence has the nucleotide sequence of CCACC.

Typically, when under the control of an endogenous or exogenous promoter (eg, an endogenous promoter), the coding sequence will immediately follow the Kozak sequence. The start of the coding region is indicated by the start codon (AUG), for example in the context of the sequence (gcc)gccRcc AUG g [SEQ ID NO: 105], and the start of the coding sequence is indicated by the base in bold. Lowercase letters denote consensus bases at this position (which may nevertheless vary), uppercase letters denote highly conserved bases, ie the'AUGG' sequence is constant or rare, and if any, varies; 'R' indicates that purines (adenine or guanine) are usually observed at this position, and the sequence in parentheses (gcc) is uncertainly significant. Thus, in one embodiment, the start codon AUG is introduced into the Kozak sequence.

Internal ribosome entry DNA sequence, as used herein, refers to a DNA sequence encoding an internal ribosome entry sequence (IRES). IRES, as used herein, refers to a nucleotide sequence that allows the initiation of translation of a messenger RNA (mRNA) sequence, such as starting within an mRNA sequence. When the cassette encodes a polycistronic mRNA, this is particularly useful. Using IRES results in polycistronic mRNA translated into a number of individual proteins or peptides. In one embodiment, the internal ribosome entry DNA sequence has the nucleotide sequence of SEQ ID NO: 6. In one embodiment, a particular IRES is used only once in the genome. This can have benefits with regard to the stability of the genome.

"High self-cleaving efficiency 2A peptide" or "2A peptide", as used herein, refers to a peptide that is efficiently cleaved after translation. Suitable 2A peptides include P2A, F2A, E2A and T2A. The inventors have noted that once a specific DNA sequence encoding a given 2A peptide is used once, the same specific DNA sequence may not be used twice. However, duplication of the DNA code can be used to generate a DNA sequence that translates to the same 2A peptide. When the cassette encodes a polycistronic mRNA, it is particularly useful to use a 2A peptide. Using the 2A peptide allows a single polypeptide chain, which has been modified after translation, to be translated, to produce a number of individual proteins or peptides.

In one embodiment, the encoded P2A peptide used has the amino acid sequence of SEQ ID NO: 7. In one embodiment, the encoded F2A peptide used has the amino acid sequence of SEQ ID NO: 8. In one embodiment, the encoded E2A peptide used has the amino acid sequence of SEQ ID NO:9. In one embodiment, the encoded T2A peptide used has the amino acid sequence of SEQ ID NO: 10.

In one embodiment, the transgene-encoded mRNA or each mRNA comprises a polyadenylation signal sequence, eg, typically at the end of the mRNA sequence, eg, as described in SEQ ID NO: 5. Thus, in one embodiment, the transgene or transgene cassette comprises at least one sequence encoding a polyadenylation signal sequence.

“PolyA”, “polyadenylation signal” or “polyadenylation sequence”, as used herein, once transcribed, can be recognized by a multiprotein complex that cleaves and polyadenylates the new mRNA molecule. It refers to a DNA sequence that usually contains an AATAAA site.

In one embodiment, the polyadenylation sequence has the nucleotide sequence of SEQ ID NO: 5.

In one embodiment, the construct does not comprise a polyadenylation sequence. In one embodiment, the modulator of gene expression is a splice acceptor sequence.

In one embodiment, the sequence encoding the protein/polypeptide/peptide, such as an antibody or antibody binding fragment, further comprises a polyadenylation signal.

In one embodiment, a virus or construct having the sequence disclosed herein, such as NG-330 ( SEQ ID NO: 16 ); NG-334 ( SEQ ID NO: 17 ); NG-345 ( SEQ ID NO: 18 ); NG-346 ( SEQ ID NO: 19 ); Viruses selected from NG-347 ( SEQ ID NO: 20 ) and NG-348 ( SEQ ID NO: 96 ) are provided.

In one embodiment, the virus is NG-347 ( SEQ ID NO: 20 ) or NG-348 ( SEQ ID NO: 96).

Formulation

The present disclosure relates to, and extends to, pharmaceutical preparations of viruses as described herein.

In one embodiment, there is provided a liquid parenteral formulation for example infusion or injection of replicable tumor cell disruption according to the present disclosure, said formulation ranging from ^{1x10 10} to 1x10 ^{14 viral particles per volume of the dose.} Provides capacity.

Parenteral preparations refer to preparations designed not to be delivered through the GI tract. Typical parenteral routes of delivery include injection, implantation or infusion. In one embodiment, the formulation is provided in a form for bolus delivery.

In one embodiment, the parenteral formulation is in the form of injection. Injections include intravenous, subcutaneous, intratumoral or intramuscular injection. Injection, as used herein, refers to the insertion of liquid into the body through a syringe. In one embodiment, the methods of the present disclosure do not include intratumoral injection.

In one embodiment, the parenteral formulation is in the form of infusion.

Infusion, as used herein, refers to the administration of a fluid at a slower rate by a drip, infusion pump, syringe driver or equivalent device. In one embodiment, the infusion is 1.5 minutes to 120 minutes, such as about 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 13 minutes, 14 minutes , 15 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 65 minutes, 70 minutes, 65 It is administered over a period in the range of minutes, 80 minutes, 85 minutes, 90 minutes, 95 minutes, 100 minutes, 105 minutes, 110 minutes or 115 minutes.

In one embodiment, a dose of less than 100 ml, eg 30 ml, of the formulation is administered, such as by a syringe driver.

In one embodiment, the injection is administered as a slow injection, for example over a period of 1.5 to 30 minutes.

In one embodiment, the formulation is for intravenous (i.v.) administration. This pathway allows rapid access to most organs and tissues and is particularly useful for the treatment of metastases, e.g. established metastases, especially those located in very vascularized areas such as the liver and lungs. It is particularly effective for delivery.

Therapeutic preparations will typically be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, liposome, or other parenteral preparation suitable for administration to humans, and can be formulated as a pre-filled device, such as a syringe or vial, especially as a single dose.

Such formulations will generally comprise a pharmaceutically acceptable diluent or carrier, such as a non-toxic isotonic carrier, which is compatible with the virus and which the virus is stable for the required period of time.

The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (eg, glycerol, propylene glycol and liquid polyethylene glycol, etc.), and suitable mixtures thereof. Proper flowability can be maintained, for example, by the use of dispersants or surfactants such as lecithin or nonionic surfactants such as polysorbate 80 or 40. In dispersion, maintenance of the required particle size can be aided by the presence of a surfactant. Examples of tonicity agents include sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.

In one embodiment, the parenteral formulation used may comprise one or more of the following: a buffering agent, e.g. 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, phosphate buffer and/or Tris buffer, sugars such as dextrose, mannose, sucrose or the like, salts such as sodium chloride, magnesium chloride Or potassium chloride, detergents such as nonionic surfactants such as brij, PS-80, PS-40 or the like. The formulation may also contain a preservative, such as EDTA or ethanol or a combination of EDTA and ethanol, which is believed to obstruct one or more pathways of possible degradation.

In one embodiment, the formulation will comprise a purified tumor cell disruption protein according to the present disclosure, e.g., 1× ^{10 10} to ^{1×10 14} viral particles per dose, such as 1× ^{10 10 to 1×10 12} viral particles per dose. . In one embodiment, the concentration of virus in the formulation ranges from ^{2×10 8} to ^{2×10 14} vp/ml, such as 2×10 ¹² vp/ml.

In one embodiment, the parenteral formulation comprises glycerol.

In one embodiment, the formulation comprises a tumor cell disruption adenovirus, HEPES (N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid), glycerol and a buffer as described herein. .

In one embodiment, the parenteral formulation is a protein of the present disclosure, HEPES e.g. 5mM, glycerol, e.g. 5-20% (v/v), e.g. to adjust the pH in the range of 7-8. It consists of hydrochloric acid and water for injection.

In one embodiment, ^{0.7 ml of a protein of the present disclosure at a concentration of 2×10 12} vp/ml is formulated in 5 mM HEPES, 20% glycerol with a final pH of 7.8.

A thorough discussion of pharmaceutically acceptable carriers is available in Remington's Pharmaceutical Sciences (Mack Publishing Company, N.J. 1991).

In one embodiment, the formulation is provided as a formulation for topical administration including inhalation.

Suitable inhalable preparations include inhalable powders, metering aerosols containing propellant gas or inhalable solutions without propellant gas. Inhalable powders according to the present disclosure will generally contain a virus as described herein along with a physiologically acceptable excipient.

These inhalable powders are monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose), oligosaccharides and polysaccharides (e.g. dextran), polyalcohols (e.g. For example, sorbitol, mannitol, xylitol), salts (eg, sodium chloride, calcium carbonate) or mixtures of these and others may be included. Monosaccharides or disaccharides such as lactose or glucose (particularly but exclusively not in the form of their hydrates) are suitably used.

Particles for placement in the lung require a particle size of less than 10 microns, such as 1-9 microns, for example 0.1 to 5 μm, in particular 1 to 5 μm. The size of the virus-bearing particle is of primary importance, and thus, in one embodiment, the protein according to the present disclosure can be adsorbed or absorbed by the particle, such as lactose particles of a given size.

Propellant gases that can be used to make inhalable aerosols are known in the art. Suitable propellant gases are selected from chlorinated and/or fluorinated derivatives of hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as methane, ethane, propane, butane, cyclopropane or cyclobutane. The propellant gases mentioned above can be used on their own or in mixtures thereof.

Particularly suitable propellant gases are halogenated alkane derivatives selected from TG 11, TG 12, TG 134a and TG227. Among the above-mentioned halogenated hydrocarbons, TG134a (1,1,1,2-tetrafluoroethane) and TG227 (1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof are particularly Suitable.

Inhalable aerosols containing propellant gases may also contain other components such as co-solvents, stabilizers, surface active agents (surfactants), antioxidants, lubricants and means for adjusting the pH. All these ingredients are known in the art.

The propellant gas-containing inhalable aerosol according to the invention may contain up to 5% by weight of active substance. Aerosols according to the invention contain, for example, 0.002 to 5% by weight, 0.01 to 3% by weight, 0.015 to 2% by weight, 0.1 to 2% by weight, 0.5 to 2% by weight or 0.5 to 1% by weight of active ingredient .

Alternatively, topical administration to the lungs can also be performed, for example, in a nebulizer connected to a device, such as a nebulizer, for example a compressor (e.g. Pari Master(R) manufactured by Pari Respiratory Equipment, Inc., Richmond, Va.) A Pari LC-Jet Plus(R) nebulizer connected to a compressor) can be used to administer a liquid solution or suspension formulation.

The virus of the present invention can be delivered dispersed in a solvent, for example in the form of a solution or suspension, for example as already described above for parenteral preparations. It can be suspended in a suitable physiological solution, for example saline or other pharmacologically acceptable solvent or buffer solution. Buffer solutions known in the art are from 0.05 mg to 0.15 mg disodium edetate, 8.0 mg to 9.0 mg NaCl, 0.15 mg to 0.25 mg polysorbate, 0.25 mg per ml of water to achieve a pH of about 4.0 to 5.0. 0.30 mg anhydrous citric acid, and 0.45 mg to 0.55 mg sodium citrate.

The therapeutic suspension or solution formulation may also contain one or more excipients. Excipients are well known in the art, and buffers (e.g., citrate buffers, phosphate buffers, acetate buffers and bicarbonate buffers), amino acids, urea, alcohols, ascorbic acid, phospholipids, proteins (e.g., Serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol and glycerol. Solutions or suspensions can be encapsulated in liposomes or biodegradable microspheres. The formulation will generally be provided in a substantially sterile form using a sterile manufacturing process.

This may include preparation and sterilization by filtration of the buffer solvent/solution used in the formulation, aseptic suspension of the antibody in a sterile buffered solvent solution, and distribution of the formulation to a sterile receptacle by methods familiar to those skilled in the art.

Sprayable formulations according to the present disclosure may be presented, for example, as single dosage units (eg, sealed plastic containers or vials) packaged in foil bags. Each vial contains a unit dose in a volume equal to 2 ml of solvent/solution buffer.

The present disclosure also extends to intranasally delivered liquid solutions or suspensions using devices as disclosed, for example, in WO2009/068877 and US2004/0153033, both of which are incorporated herein by reference.

cure

In a further aspect, the disclosure extends to a virus or agent thereof as described herein for use in treatment, in particular for the treatment of cancer.

In one embodiment, the method of treatment is for use in the treatment of a tumor.

Tumor, as used herein, is intended to mean an abnormal mass of tissue resulting from excessive cell division that is uncontrolled and progressive, also called neoplasms. Tumors can be benign (not cancerous) or malignant. Tumors include all forms of cancer and metastasis. In one embodiment, the tumor is cancerous.

In one embodiment, the tumor is a solid tumor. Solid tumors can be localized or metastasized.

In one embodiment, the tumor is of epithelial origin.

In one embodiment, the tumor is a malignant tumor, such as colorectal cancer, hepatocellular carcinoma, prostate cancer, pancreatic cancer, breast cancer, ovarian cancer, thyroid cancer, kidney cancer, bladder cancer, head and neck cancer, or lung cancer.

In one embodiment, the tumor is a colorectal malignancy.

Malignant tumor, as used herein, refers to cancerous cells.

In one embodiment, the tumor cell disruption adenovirus is used in the treatment or prevention of metastasis.

In one embodiment, the method or formulation herein is used in the treatment of drug resistant cancer.

In one embodiment, the virus is administered in combination with administration of an additional cancer treatment or therapeutic agent.

In one embodiment, for use in the manufacture of a medicament for the treatment of cancer, e.g. the cancer described above, a virus or agent according to the present disclosure is provided.

In a further aspect, there is provided a method of treating cancer comprising administering a therapeutically effective amount of a virus or agent according to the present disclosure to a patient in need thereof, eg, a human patient.

In one embodiment, the tumor cell disruption virus or agent is administered herein in combination with another therapeutic agent.

"In combination", as used herein, is intended to include the case where the tumor cell disruption virus is administered prior to, concurrently with and/or after cancer treatment or treatment. However, in general, the treatment regimen for combination therapy

Cancer treatment includes surgery, radiation therapy, targeted therapy and/or chemotherapeutic agents.

Cancer treatment, as used herein, refers to treatment and/or maintenance treatment with a therapeutic compound or biological substance, such as an antibody intended to treat cancer.

In one embodiment, the cancer treatment is any other anticancer therapeutic agent, such as a chemotherapeutic agent; Targeted anticancer agents such as antibody drug conjugates; Radiotherapy agents, radioisotope therapeutic agents, or any combination thereof.

In one embodiment, a protein of the present disclosure, such as a tumor cell disruption adenovirus, is used for treatment, such as surgery, to shrink the tumor and/or treat metastasis and/or prevent metastasis or further metastasis. It can be used as a pretreatment (neoadjuvant therapy). Tumor cell disruption adenovirus can be used for treatment, such as post-operative (adjuvant therapy), to treat metastasis and/or prevent metastasis or further metastasis.

In one embodiment, a virus or agent of the present disclosure is used in maintenance treatment.

Simultaneously, as used herein, is the administration of an additional cancer therapeutic agent at the same time or approximately the same time as the tumor cell disruption adenovirus agent. The therapeutic agents can be contained within the same formulation or administered as separate formulations.

In one embodiment, the virus is administered in combination with administration of a chemotherapeutic agent.

Chemotherapeutic agents, as used herein, are intended to mean certain anti-neoplastic chemicals or drugs that are selectively destructive to malignant cells and tissues. For example, alkylating agents, antimetabolites, anthracyclines, plant alkaloids, topoisomerase inhibitors and other antitumor agents. Examples of specific chemotherapeutic agents include doxorubicin, 5-fluorouracil (5-FU), paclitaxel, capexitabine, irinotecan, and platins such as cisplatin and oxaliplatin. The dosage can be selected by the skilled person based on the nature of the cancer being treated.

In one embodiment, the therapeutic agent is ganciclovir, which can help modulate the immune response and/or tumor vascularization.

In one embodiment, the treatment used in the methods herein is metronum, which is continuous or frequent treatment with low doses of anticancer drugs, usually given concurrently with other treatment methods.

Subgroup B tumor cell disruption adenoviruses, especially Ad11 and those derived therefrom, such as EnAd, may be particularly synergistic with chemotherapeutic agents, because they kill cancer cells, primarily independent of apoptosis, mainly by necrotic mechanisms. This is because it appears to have a mechanism of action. Moreover, immunosuppression that occurs during chemotherapy may allow tumor cell disruption viruses to act with higher efficiency.

The therapeutic dose, as used herein, is suitable for achieving the intended therapeutic effect when used in a suitable treatment regimen, for example alleviating the symptoms or conditions of the disease without causing particularly dose limiting side effects. , Means the amount of virus, such as tumor cell disruption adenovirus. The dose can be thought of as a therapeutic dose in the treatment of cancer or metastasis, when the number of viral particles can be sufficient to cause: tumor or metastatic growth may be slowed or stopped, or the tumor or metastasis may be large Found to contract, and/or prolonged patient life. A suitable therapeutic dose is generally a balance between therapeutic effect and tolerant toxicity, where for example side effects and toxicity are tolerated, taking into account the benefits achieved by the treatment.

In one embodiment, it is provided systemically administering multiple doses of a parenteral formulation of a tumor cell disrupting adenoprotein according to the present disclosure in a single treatment cycle, e.g., the total dose given in each administration is 1x10 per dose. ^It ranges from 10 to 1x10 ¹⁴ virus particles.

In one embodiment, one or more doses (e.g., each dose) of the virus or a composition comprising the same are administered such that the rate of viral particle delivery ^{ranges from 2x10 10} particles per minute to 2x10 ^{12 particles per minute.}

In one embodiment, the virus or therapeutic construct according to the present disclosure (including formulations comprising the same) is administered weekly, for example once a week, the dose is administered on the 1st, 3rd, 5th days, One subsequent dose is administered each subsequent week.

In one embodiment, the virus or therapeutic construct (including formulations comprising the same) according to the present disclosure is administered every 2 weeks or every 3 weeks, for example 1 every 1 day, 3 days and 5 days per week. It is administered once, and is also administered on days 1, 3 and 5 thereof at 2 or 3 weeks. This dosing regimen can be repeated as many times as appropriate.

In one embodiment, the virus or therapeutic construct (including formulations comprising the same) according to the present disclosure is administered monthly, for example in a treatment cycle or as maintenance treatment.

In one embodiment, viruses and constructs of the present disclosure are produced by recombinant techniques. The skilled person will understand that armed adenovirus genomes can be prepared by other technical means, by fully synthesizing a plasmid comprising a portion of the genome or all of the genome. Those skilled in the art will understand that since the restriction site nucleotide is an artifact after insertion of the gene using the cloning method, the region of the insertion may not contain the restriction site nucleotide in the event of synthesizing the genome.

In one embodiment, the armed adenovirus genome is fully synthetically prepared according to, for example, SEQ ID NO: 109 used with the transgene cassette in SEQ ID NOs: 18, 20, 96, 101, 102, 103.

The present disclosure further extends to adenoviruses of formula (I) or subformulae thereof that can be obtained or obtained by inserting a transgene or transgene cassette herein.

"There is" means to include as used herein.

In the context of this specification, "comprising" is to be interpreted as "including".

Embodiments of the invention comprising certain features/elements are also intended to extend to “consisting of” or “consisting essentially of” alternative embodiments of the relevant elements/features.

Where technically appropriate, embodiments of the present invention may be combined.

Technical literature, such as patents and applications, are incorporated herein by reference.

Any embodiments specifically and expressly mentioned herein may be used alone or in combination with one or more additional embodiments to form a basis for disclaimer.

In this specification, the head is used to divide the document into sections, and is not intended to be used to interpret the meaning of the present disclosure provided herein.

The invention is further described by way of illustration only in the following examples.

Example

Example 1: expressing the T cell activating antigen CD80 EnAd Manufacture of virus

Using plasmid pEnAd2.4, plasmid pNG-330 was generated by direct insertion of a cassette encoding human T cell activating antigen CD80 (SEQ ID NO: 11). The pNG-330 cassette contains a 5'short splice acceptor sequence CAGG, a human CD80 cDNA sequence and a 3'polyadenylation sequence (SEQ ID NO: 5). An illustration of the inserted transgene cassette is shown in Figure 3A. Construction of the plasmid was confirmed by DNA sequencing.

Virus manufacturing and identification

Reference herein to a virus, such as NG-330-00, is simply a reference to a specific batch of virus NG-330 indicated “00”. Similar nomenclature can be used for other viruses.

Plasmid pNG-330 was linearized by restriction digestion with the enzyme AscI to generate viral genome NG-330 (SEQ ID NO: 16). The digested DNA was purified by phenol/chloroform extraction and precipitated in 300 μl of >95% molecular biology grade ethanol and 10 μl of 3M sodium acetate at -20° C. for 16 hours. The precipitated DNA was pelleted by centrifugation at 14000 rpm for 5 minutes, washed in 500 µl of 70% ethanol, and then centrifuged again at 14000 rpm for 5 minutes. Clean DNA pellets were air dried, resuspended in 500 μl OptiMEM containing 15 μl Lipofectamine transfection reagent, and incubated at room temperature for 30 minutes. Thereafter, the transfection mixture was added dropwise to a T-25 flask containing 293 cells grown to 70% saturation. After incubation of the cells and transfection mixture for 2 hours at 37° C., 5% CO ₂ , 4 ml of cell medium (DMEM high glucose with glutamine supplemented with 2% FBS) was added to the cells, and the flask was added at 37° C. , Incubated in 5% CO _2.

Transfected 293 cells were monitored every 24 hours and supplemented with additional medium every 48-72 hours. Virus production was monitored by observation of a significant cytopathic effect (CPE) in the cell monolayer. Once extensive CPE was observed, virus was harvested from 293 cells by 3 freeze-thaw cycles. The virus stock was amplified by re-infecting 293 cells using the harvested virus. Viability virus production during amplification was confirmed by observation of significant CPE in the cell monolayer. If CPE was observed, virus was harvested from 293 cells by 3 freeze-thaw cycles. After the amplified stock was used for further amplification, the virus was purified by double cesium chloride banding to prepare an NG-330 virus stock.

Example 2: carcinoma In cell line With EnAd Identification of compared NG-330 virus activity

NG-330 or EnAd virus replication (evaluated by qPCR), and CD80 membrane expression (evaluated by flow cytometry (FIGS. 4 and 5 )) were compared in colon carcinoma cell line HT-29 and lung carcinoma cell line A549. NG-330 is a virus derived from EnAd containing a human T cell activating antigen, a transgene cassette encoding CD80 and L5 (fiber) after the EnAd late gene. An illustration of the inserted cassette is shown in Fig. 3A. The preparation of NG-330 virus is described in Example 1. A549 or HT-29 carcinoma cell lines were seeded in 6 well plates at a cell density of 7.5e5 cells/well for A549 cells or 2.e6 cells/well for HT-29 cells. After the plate was incubated for 18 hours at 37° C., 5% CO ₂ , cells were infected with 100 EnAd or NG-330 virus particles (ppc) per cell or left uninfected. Assays were performed 24 hours, 48 hours or 72 hours post infection.

qPCR Virus replication assessed by

For quantification of viral DNA by qPCR, HT-29 and A549 cell lines infected or uninfected with 100 ppc of EnAd or NG-330 for 24 hours, 48 hours or 72 hours were used. Cell supernatant was collected and clarified by centrifugation at 1200 rpm for 5 minutes. DNA was extracted from 10 μl of the supernatant using a Sigma Genelute DNA extraction kit according to the manufacturer's protocol. A standard curve using EnAd virus particles (2.5e10-2.5e5vp) was also prepared and extracted using the Sigma Genelute kit. Each extracted sample or standard was analyzed by qPCR using an EnAd E3 gene specific primer-probe set.

Quantification of the number of viral genomes detected per cell demonstrates that NG-330 and EnAd viral replication are comparable in both HT-29 (Figure 4A) and A549 cell lines (Figure 4B). No viral genome was detected in uninfected cells (data not shown).

Flow cytometry CD80 cell surface expression assessed by

The HT-29 and A549 cell lines infected or left uninfected with 100 ppc of EnAd or NG-330 for 24 hours, 48 hours or 72 hours were used for analysis of CD80 transgene expression on the cell surface. Tumor cells were removed from the plate surface by treatment with trypsin, centrifuged and then resuspended in 1% BSA/PBS. Thereafter, the samples were incubated with a buffer, a mouse isotype control antibody conjugated to Cy5, or an anti-human CD80 antibody conjugated to Cy5 (clone 2D10) for 1 hour at 5°C. All samples were also co-stained with live/dead Zombie Aqua to discriminate viable cells. Samples were washed 3 times with 1% BSA/PBS and then analyzed by flow cytometry (FACS, Attune) for cell viability and CD80 protein expression on the cell surface. The assay showed that CD80 could be detected on the cell surface in both A549 (Figure 5A) or HT-29 (Figure 5B) cells treated with NG-330, rather than being treated with EnAd or left untreated. Showed.

Comparison of viral tumor cell disruption effect

HT-29 colon carcinoma cells were seeded in 96 well plates at a cell density of 2.5e4 cells/well. Plates were incubated at 37° C., 5% CO ₂ for 4 hours, then cells were infected with EnAd or NG-330 virus particles in an infection density range of 100-0.39 particles per cell (ppc). 72 hours after infection, HT-29 cell viability was evaluated using Cell Titre 96 MTS reagent (Promega: G3581). Quantification of cell survival (%) at each infection density demonstrates that the NG-330 tumor cell disruption potency is comparable to EnAd in HT29 cells (FIG. 6 ).

Example 3: T cell activating antigen CD80 and cytokine IFNα Manifest EnAd Manufacture of virus

Using plasmid pEnAd2.4, plasmid pNG-343 was generated by direct insertion of a cassette encoding human T cell activating antigen CD80 (SEQ ID NO: 11) and human cytokine interferon α (IFNα, SEQ ID NO: 12). The pNG-343 cassette contains the 5'short splice acceptor sequence CAGG; Human IFNa cDNA; High efficiency self-cleavable P2A peptide sequence (SEQ ID NO: 7); It contains a human CD80 cDNA sequence and a 3'polyadenylation sequence (SEQ ID NO: 5). An illustration of the inserted transgene cassette is shown in Figure 3B. Construction of the plasmid was confirmed by DNA sequencing.

Virus manufacturing and identification

Plasmid pNG-343 was linearized by restriction digestion with the enzyme AscI to generate viral genome NG-343 (SEQ ID NO: 17). Virus NG-343 was amplified and purified according to the method described in Example 1.

Example 4: FMS-like Tyrosine Kinase -3 of the ligand Extracellular domain, Chemokines MIP1α and cytokines IFNα Manifest EnAd Manufacture of virus

Direct insertion of a cassette encoding a soluble variant of the FMS-like tyrosine kinase-3 ligand (Flt3L, SEQ ID NO: 13), MIP1α (isoform LD78β, SEQ ID NO: 14) and IFNα (SEQ ID NO: 12) using plasmid pEnAd2.4 Plasmid pNG-345 was generated by. The pNG-345 cassette contains the 5'short splice acceptor sequence CAGG; Human Flt3L cDNA; High efficiency self-cleavable P2A peptide sequence (SEQ ID NO: 7); Human MIP1α cDNA; High efficiency self-cleavable T2A peptide sequence (SEQ ID NO: 10); Contains human IFNa cDNA and 3'polyadenylation sequence (SEQ ID NO: 5). An illustration of the inserted transgene cassette is shown in Figure 3D. Construction of the plasmid was confirmed by DNA sequencing.

Virus manufacturing and identification

Plasmid pNG-345 was linearized by restriction digestion with the enzyme AscI to generate viral genome NG-345 (SEQ ID NO: 18). Virus NG-345 was amplified and purified according to the method described in Example 1.

Example 5: T cell activating antigen CD80, Chemokines MIP1α And Flt3 Ligand expressing EnAd Manufacture of virus

Using plasmid pEnAd2.4, direct insertion of a cassette encoding human T cell activating antigen CD80 (SEQ ID NO: 11), human macrophage inflammatory protein 1α (MIP1α, SEQ ID NO: 14) and human Flt3 ligand (SEQ ID NO: 13) Plasmid pNG-346 was generated by this. The pNG-346 cassette contains the 5'short splice acceptor sequence CAGG; Human IFNa cDNA; High efficiency self-cleavable P2A peptide sequence (SEQ ID NO: 7); Human MIP1α cDNA (isoform LD78β); High efficiency self-cleavable T2A peptide sequence (SEQ ID NO: 10); It contains a human Flt3 ligand cDNA sequence and a 3'polyadenylation sequence (SEQ ID NO: 5). An illustration of the inserted transgene cassette is shown in Figure 3e. Construction of the plasmid was confirmed by DNA sequencing.

Virus manufacturing and identification

Plasmid pNG-346 was linearized by restriction digestion with the enzyme AscI to generate viral genome NG-346 (SEQ ID NO: 19). Virus NG-346 was amplified and purified according to the method described in Example 1.

Example 6: T cell activating antigen CD80, Chemokines MIP1α And cytokines IFNα Manifest EnAd Manufacture of virus

Cassette encoding human T cell activating antigen CD80 (SEQ ID NO: 11), human macrophage inflammatory protein 1α (MIP1α, SEQ ID NO: 14) and human cytokine interferon α (IFNα, SEQ ID NO: 12) using plasmid pEnAd2.4 Plasmid pNG-347 was generated by direct insertion of. The pNG-347 cassette contains the 5'short splice acceptor sequence CAGG; Human IFNa cDNA; High efficiency self-cleavable P2A peptide sequence (SEQ ID NO: 7); Human MIP1α cDNA (isoform LD78β); High efficiency self-cleavable T2A peptide sequence (SEQ ID NO: 10); It contains a human CD80 cDNA sequence and a 3'polyadenylation sequence (SEQ ID NO: 5). An illustration of the inserted transgene cassette is shown in Figure 3F. Construction of the plasmid was confirmed by DNA sequencing.

Virus manufacturing and identification

Plasmid pNG-347 was linearized by restriction digestion with the enzyme AscI to generate viral genome NG-347 (SEQ ID NO: 20). Virus NG-347 was amplified and purified according to the method described in Example 1.

Example 7: ε chain of the T cell activating antigen CD80 and human CD3 complex ( CD3ε ) Just pinned to Short chain Fv Expressing a fragment antibody EnAd Manufacture of virus

Using plasmid pEnAd2.4, plasmid pNG-348 was prepared by direct insertion of a cassette encoding the human T cell activating antigen CD80 (SEQ ID NO: 11) and the membrane-immobilized chimeric form of the single chain Fv anti-human CD3e (SEQ ID NO: 15). Was created. The pNG-348 cassette contains the 5'short splice acceptor sequence CAGG; Membrane immobilized anti-human CD3e scFv cDNA; High efficiency self-cleavable P2A peptide sequence (SEQ ID NO: 7); It contains a human CD80 cDNA sequence and a 3'polyadenylation sequence (SEQ ID NO: 5). An illustration of the inserted transgene cassette is shown in Figure 3C. Construction of the plasmid was confirmed by DNA sequencing.

Virus manufacturing and identification

Plasmid pNG-348 was linearized by restriction digestion with the enzyme AscI to generate viral genome NG-348 (SEQ ID NO: 96). Virus NG-348 was amplified and purified according to the method described in Example 1.

Example 8: T cell activating antigen CD80 and cytokine IFNα NG-343, which expresses two transgenes EnAd Viral activity

carcinoma In cell line With EnAd Identification of compared NG-343 virus activity

NG-343 or EnAd virus replication (evaluated by qPCR), CD80 transgene expression (evaluated by flow cytometry) or IFNα transgene expression (evaluated by ELISA) in a colon carcinoma cell line that is HT-29, or a lung carcinoma cell line that is A549 ) Were compared. NG-343 is a virus derived from EnAd containing a human T cell activating antigen, CD80, and a transgene cassette encoding the human cytokine interferon alpha 2b, L5 (fiber) located after the late EnAd gene. An illustration of the inserted cassette is shown in Fig. 3B. The preparation of NG-343 virus is described in Example 3. A549 or HT-29 carcinoma cell lines were seeded in 12 well plates at a cell density of ^{7.5×10 5 cells/well for A549 cells or 1.4×10 6} cells/well for HT-29 cells. After incubating the plates at 37° C., 5% CO ₂ for 18 hours, the cells were infected or left uninfected with 100 virus particles (ppc) per cell. Assays were performed 24 hours, 48 hours or 72 hours post infection.

qPCR Virus replication assessed by

For quantification of viral DNA by qPCR, HT-29 cells infected or uninfected with 100 ppc of EnAd or NG-343 for 24 hours, 48 hours or 72 hours were used. Cell supernatant was collected and clarified by centrifugation at 1200 rpm for 5 minutes. DNA was extracted from 10 μl of the supernatant using a Sigma Genelute DNA extraction kit according to the manufacturer's protocol. Standard curves using EnAd virus particles ( ^{2.5×10 10} to 2.5 ^{×10 5} vp) were also prepared and extracted using the Sigma Genelute kit. Each extracted sample or standard was analyzed by qPCR using an EnAd E3 gene specific primer-probe set.

Quantification of the number of viral genomes detected per cell demonstrates that NG-343 and EnAd viral replication are comparable at all time points analyzed (FIG. 7A ). No viral genome was detected in uninfected cells (data not shown).

By ELISA IFNα Analysis of expression

Supernatants of HT-29 or A549 cell lines infected or uninfected for 24 hours, 48 hours or 72 hours were analyzed with 10 ppc of EnAd or NG-343 for expression of IFNα secreted by ELISA.

The culture supernatant was removed from each well and centrifuged at 1200 rpm for 5 minutes to remove cell debris. The supernatant is diluted with 5% BSA/PBS assay buffer (1:2 or 1:50 or 1:100) and ELISA using Verikine Human IFN Alpha Kit (Pbl assay science) according to the manufacturer's protocol. Performed

The concentration of secreted IFNa was determined by extrapolation from the standard curve. Increased IFNα expression in the cell supernatant over the course of infection was detected in both HT-29 and A549 cell lines (FIG. 7B ).

Flow cytometry CD80 cell surface expression assessed by

The A549 cell line infected or uninfected with 100 ppc of EnAd or NG-343 for 48 or 72 hours was used for analysis of CD80 transgene expression on the cell surface. At appropriate time points after infection, A549 cells were removed from the plate surface by treatment with trypsin, centrifuged and then resuspended in 1% BSA/PBS. Thereafter, the samples were incubated with a buffer, a mouse isotype control antibody conjugated to Cy5, or an anti-human CD80 antibody conjugated to Cy5 (clone 2D10) for 1 hour at 5°C. All samples were also co-stained with live/dead Zombie Aqua to discriminate viable cells. Samples were washed 3 times with 1% BSA/PBS and then analyzed by flow cytometry (FACS, Attune) for cell viability and CD80 protein expression on the cell surface. Analysis of CD80 expression for live/dead staining, CD80 can be detected on the cell surface of NG-343 treated cells, not EnAd or uninfected control (UIC) cells, at both 48 and 72 hours post infection. Showed that there is (Fig. 8). Cell viability at 72 hours after virus treatment is not sufficient to perform a comprehensive CD80 expression assay, but high levels of CD80 could be detected in both live and dead cells treated with NG-343 at this point ( 8D, lower panel).

Then, 48 hours after infection with 100 ppc, CD80 protein expression was compared in HT-29 and A549 cells. Samples were analyzed and stained as described above prior to analysis of cell viability and CD80 protein expression on the cell surface. Analysis of CD80 expression at this time point on the only cells stained as live cells showing CD80 was not in the EnAd treated control, but about 91% of NG-343 treated HT-29 cells and NG-343 treated A549 cells. It could be detected on about 98% of the surface.

Example 9: carcinoma , Selectivity of transgene expression and NG-343 viral activity in stromal fibroblasts and epithelial cell lines.

To show that IFNα and CD80 transgenes encoded in NG-343 virus are only selectively expressed in cells acceptable to NG-343 or EnAd infection, cancer cells known to be acceptable for EnAd infection (HT-29), Viral replication (evaluated by qPCR), IFNα expression (ELISA) in fibroblast cell lines previously identified as unacceptable (WI-38 and MRC-5) and bronchial epithelial cell lines (BE) that showed only limited tolerance for EnAd infection. ) And CD80 expression (evaluated by flow cytometry) were measured. Briefly, cells are seeded in 12 well plates and 18 hours after seeding with 100 ppc of NG-343 or EnAd virus for WI38, MRC5 or BE cells or 10 ppc of NG-343 or EnAd virus for HT-29 cells. Infected. After the cells were incubated with virus particles for 4 hours, the infection medium was removed from the cells and replaced by fresh culture medium. At 1 hour or 72 hours after the 4 hour infection period, the cell supernatant was harvested for qPCR or ELISA analysis, and the cells were treated with trypsin to remove it from the plate for analysis by flow cytometry.

NG-343 and EnAd Selective virus replication

For qPCR, cell supernatant was collected and clarified by centrifugation for 5 minutes at 1200 rpm. DNA was extracted from 10 μl of the supernatant using a Sigma Genelute DNA extraction kit according to the manufacturer's protocol. Standard curves using EnAd virus particles (2.5x10 ¹⁰ to 2.5x10 ⁵ vp) were also prepared and extracted using the Sigma Genelute kit. Each extracted sample or standard was analyzed by qPCR using an EnAd E3 gene specific primer-probe set.

Quantification of the number of viral genomes detected per cell demonstrates that NG-343 and EnAd viral replication are comparable in all cell lines analyzed (FIG. 9A ).

NG-343 selective transgene expression

For detection of IFNα expression, cell supernatants were collected and clarified by centrifugation at 1200 rpm for 5 minutes. The supernatant was diluted with 5% BSA/PBS assay buffer (1:2 or 1:50 or 1:100), and ELISA was performed using Berikin Human IFN Alpha Kit (Pbl assay science) according to the manufacturer's protocol.

The concentration of secreted IFNa was determined by extrapolation from the standard curve. IFNα expression could only be detected in the supernatant of NG-343 infected HT-29 cells, and was not detectable in fibroblast cell lines, or in bronchial epithelial cell lines (Fig. 9b) (below the lower limit of quantification [<LLOQ]).

For CD80 cell surface expression, the samples were then incubated with a buffer, a mouse isotype control antibody conjugated to Cy5, or an anti-human CD80 antibody conjugated to Cy5 (clone 2D10) for 1 hour at 5°C. All samples were also co-stained with live/dead Zombie Aqua to discriminate viable cells. Samples were washed 3 times with 1% BSA/PBS and then analyzed by flow cytometry (FACS, Attune) for cell viability and CD80 protein expression on the cell surface. Consistent with IFNα expression data, CD80 expression could only be detected in HT-29 cells, and there was no detectable expression in fibroblasts or bronchial epithelial cell lines (FIG. 9C ).

Taken together, these data show that both IFNα and CD80 transgenes are selectively expressed in cells that are acceptable for EnAd virus infection, i. Prove that it does not change.

Example 10: activity of NG-343 transgene expression on immune cell activation

In order to determine whether treatment of tumor cells with NG-343 virus results in an enhanced innate immune cell response compared to the absence of treatment or EnAd treatment, freshly isolated peripheral blood mononuclear cells (PBMCs) were treated with NG-343 or It was co-cultured with tumor cells infected or uninfected by EnAd. Immune cell activation was evaluated by flow cytometric analysis of the innate immune cell population or ELISA analysis of the co-culture supernatant. Briefly, A549 lung carcinoma cells were seeded in 12 well plates at ^{a density of 4x10 5} cells/well. After 20 hours, cells were infected with 10 ppc of EnAd or NG-343 virus or left uninfected, and then _{incubated at 37° C., 5% CO 2} for 24 hours. Then, PBMCs isolated from healthy human donors by density gradient centrifugation were added to A549 culture wells at a ratio of 5 PBMCs to 1 A549 cells. 48 hours after the addition of PBMC, co-culture supernatants were harvested from the plate. To analyze dendritic cell activation at this point, cells were subjected to buffer, mouse isotype control antibody conjugated to Alexa Fluor 488, PE, PerCP/Cy5.5, BV605 or BV412, anti-CD14 antibody conjugated to Alexa Fluor 488, Anti-CD80 antibody conjugated to PE, anti-HLA-DR conjugated to PerCP.Cy5.5, anti-CD3 conjugated to BV605 or anti-PD-L1 antibody conjugated to BV421 and incubated at 5°C for 1 hour I did. All samples were also co-stained with live/dead Zombie Aqua to discriminate viable cells. The sample was washed 3 times with 1% BSA/PBS, and then analyzed by flow cytometry (FACS, Attune). Viable cells that are positive for HLA-DR but stained negative for both CD14 and CD3 are defined as dendritic cell populations. The expression of DC activation markers, CD80 and PD-L1 in this population was compared (FIG. 10 ). This analysis revealed that tumor cells infected with NG-343 can induce increased surface levels of both CD80 and PD-L1 on the surface of DCs when compared to EnAd infected or uninfected tumor cell cultures.

Example 11: T cell activating antigen CD80, Chemokines MIP1α And cytokines IFNα NG-347, which expresses three transgenes EnAd Viral activity

carcinoma In the cell line With EnAd Identification of compared NG-347 virus activity

CD80 transgene expression (evaluated by flow cytometry) and IFNα or MIP1α (CCL3) transgene expression (evaluated by ELISA) in a colon carcinoma cell line treated with NG-347 and EnAd, or A549, a lung carcinoma cell line. Compared. NG-347 is a virus derived from EnAd containing a transgene cassette encoding human T cell activating antigen, CD80, human cytokine interferon alpha 2b and human chemokine MIP1α (LD78β isoform). Transgene expression is under the control of a major late promoter endogenous to the virus. An illustration of the inserted cassette is shown in Fig. 3F. The preparation of NG-347 virus is described in Example 6. A549 or HT-29 carcinoma cell lines were seeded in 12 well plates at a cell density of ^{7.5×10 5 cells/well for A549 cells or 1.4×10 6} cells/well for HT-29 cells. After the plate was incubated for 18 hours at 37° C., 5% CO ₂ , cells were infected with 100 EnAd or NG-347 virus particles (ppc) per cell or left uninfected. Assays were performed 24 hours, 48 hours or 72 hours post infection.

By ELISA IFNα or MIP1α Analysis of expression

Supernatants of HT-29 or A549 cell lines infected or uninfected for 24 hours, 48 hours or 72 hours were analyzed with 10 ppc of EnAd or NG-347 for expression of secreted IFNα or secreted MIP1α by ELISA. .

Culture supernatant was prepared according to the method described in Example 9. IFNα ELISA was performed using Berikin Human IFN Alpha Kit (Pbl assay science), and MIP1α ELISA was performed using a dormant CCL3 Quantikine ELISA kit (R&D systems). Both assays were performed according to the manufacturer's protocol.

The concentration of secreted IFNα or MIPα was determined by extrapolation from the standard curve. Increased IFNα and MIP1α expression in the cell supernatant over the course of infection was detected in both HT-29 and A549 cell lines (FIGS. 11A and 11B ).

Flow cytometry Analysis of CD80 expression by

CD80 protein expression on the surface of HT-29 and A549 cells was compared 48 hours post infection. Cells were harvested and stained according to the method described in Example 9. Cells were analyzed for cell viability and CD80 protein expression on the cell surface by flow cytometry. Analysis of CD80 expression on viable cells at this point can be detected on the surface of about 96% of CD80 NG-347 treated HT-29 cells and about 99% of NG-347 treated A549 cells, but EnAd treated It was shown that no staining was detected in the control group (FIG. 11C).

Example 12: cytokines Flt3 Ligand, Chemokines Mip1α And cytokines IFNα NG-345, which expresses three transgenes EnAd Viral activity

carcinoma In the cell line With EnAd Identification of compared NG-345 virus activity

The Flt3 ligand, IFNα and MIP1α transgene expression (evaluated by ELISA) in the HT-29, NG-345 and EnAd treated colon carcinoma cell line, or the A549 lung carcinoma cell line, was compared. NG-345 is a virus derived from EnAd containing a soluble variant of the human Flt-3 ligand, a transgene cassette encoding the human cytokine interferon alpha 2b and the human chemokine MIP1α (LD78β isoform). Transgene expression is under the control of a major late promoter endogenous to the virus. An illustration of the inserted cassette is shown in Fig. 3D. The preparation of the NG-345 virus is described in Example 4. A549 or HT-29 carcinoma cell lines were seeded in 12 well plates at a cell density of ^{7.5×10 5 cells/well for A549 cells or 1.4×10 6} cells/well for HT-29 cells. After the plate was incubated for 18 hours at 37° C., 5% CO ₂ , cells were infected with 100 EnAd or NG-345 virus particles (ppc) per cell or left uninfected. Assays were performed 24 hours, 48 hours or 72 hours post infection.

By ELISA FLt -3 ligand, IFNα or MIP1α Analysis of expression

HT-29 or A549 infected or uninfected with 10 ppc of EnAd or NG-345 for expression of Flt3-ligand secreted by ELISA, secreted IFNα or secreted MIP1α for 24 hours, 48 hours or 72 hours The supernatant of the cell line was analyzed.

Culture supernatant was prepared according to the method described in Example 9. Perform IFNα ELISA using Verikin Human IFN Alpha Kit (Pbl assay science), MIP1α ELISA using dormant CCL3 Quantikin ELISA kit (R&D systems), Flt3L using Flt3L human ELISA kit (Abcam) ELISA was performed. All assays were performed according to the manufacturer's protocol.

The concentration of secreted IFNα, MIPα or FLt3L was determined by extrapolation from the standard curve. Increased IFNα, MIP1α and Flt3L expression in the cell supernatant over the course of infection was detected in both HT-29 and A549 cell lines (FIGS. 12A-C ).

Example 13. Colon carcinoma Tumor cell disruption activity and infectivity of NG-347 and NG-348 viruses in cells

Viral tumor cell disruption effect

HT-29 colon carcinoma cells were seeded in 96 well plates at a cell density of 2.5e4 cells/well. Plates were incubated for 4 hours at 37° C., 5% CO ₂ , then cells were infected with EnAd, NG-347 or NG-348 virus particles in an infection density range of 100-0.39 particles per cell (ppc). . At 72 hours after infection, HT-29 cell viability was evaluated using Cell Titer 96 MTS reagent (Promega: G3581). Quantification of cell survival (%) at each infection density demonstrates that NG-347 and NG-348 tumor cell disruption potency is comparable to EnAd (Figs. 13A and 13B).

Virus particle infectivity

HT-29 colon carcinoma cells were seeded in 12 well plates at a cell density of 4e5 cells/well. After incubating the plates at 37° C., 5% CO ₂ for 24 hours, the cells were infected with EnAd, NG-347 or NG-348 virus particles at an infection density range of 1.6e7-2e6 vp/ml. Infection of HT-29 cells was detected by antibody staining of the viral protein hexon. For each dilution tested, across 6 replicate wells, stained cells were manually quantified to count a visible range of 6 per well. The particle to infectious ratio (P:I) was calculated for each virus from the virus titer, demonstrating that both NG-347 and NG-348 had similar infectivity ratios to the EnAd reference control (FIG. 13C ).

Example 14. NG-347 and NG-348 infected carcinoma Cell surface expression of T cell activating antigen, CD80, in cell lines

CD80 transgene expression (evaluated by flow cytometry) in NG-347, NG-348 and EnAd treated colon carcinoma cell line, DLD-1 or lung carcinoma cell line, A549 was compared. A549 or DLD-1 carcinoma cell lines were seeded in 12 well plates at a cell density of 7.5e5 cells/well. After the plates were incubated for 18 hours at 37° C., 5% CO ₂ , cells were infected or left uninfected with 10 EnAd, NG-348 or NG-347 virus particles (ppc) per cell. CD80 protein expression on the surface of A549 or DLD-1 cells was compared at 24 hours, 48 hours, 72 hours or 96 hours post infection. At each time point, cells were harvested and stained according to the method described in Example 9. Cells were analyzed for cell viability and CD80 protein expression on the cell surface by flow cytometry. Analysis of CD80 expression 72 hours post infection in A549 cells showed that CD80 could be detected on the surface of more than 95% of NG-347 or NG-348 treated cells (FIGS. 14A and 14B ). At 96 hours post infection, virus treatment lysed most of the A549 cells and thus FAC analysis was not performed. For DLD-1 cells, expression could be detected in more than 50% of cells 96 hours after treatment with NG-348 and more than 70% of cells after NG-347 treatment (FIGS. 15A and 15B ). No staining was detected in either EnAd or untreated controls.

Example 15. NG-348 infected carcinoma By cell line Mediated T cell activation and Degranulation

A549 lung carcinoma cells infected or uninfected with NG-348 or EnAd virus particles were co-cultured with T cells isolated from human PBMC donors. Selectivity of the expression of NG-348 virus encoded CD80 on the surface of both A549 and T cells was evaluated by flow cytometry. Cell surface activation marker (by flow cytometry), CD107a cell surface expression (by flow cytometry) as a marker for degranulation, and secretion of stimulating cytokines, IL-2 and IFNγ (by ELISA) to determine T cell activation. Evaluated.

A549 cells were seeded in 12 well plates at a cell density of 5e5 cells/well. After the plates were incubated for 18 hours at 37° C., 5% CO ₂ , cells were infected with 10 EnAd or NG-348 virus particles (ppc) per cell or left uninfected. ^{48 hours post infection, CD3 +} T cells isolated by negative selection from PBMC (MAC) were added to the A549 cell monolayer at a ratio of 8 T cells to 1 tumor cell. Co-culture was performed for 16 hours, after which time cell supernatants were collected for ELISA analysis, and tumor cells and T cells were harvested for flow cytometric analysis.

The culture medium containing non-adherent cells was removed from the co-culture well and centrifuged (300xg). The supernatant was carefully removed, diluted 1 in 2 with PBS 5% BSA and saved for ELISA analysis. The adherent cell monolayer was washed once with PBS and then detached using trypsin. Trypsin was inactivated using complete medium, and cells were added to the cell pellet collected from the culture supernatant. The cells were centrifuged (300xg), the supernatant was discarded, and the cell pellet was washed in 200 μl of PBS. The cells were centrifuged again and then resuspended in 50 μl of FAC buffer (5% BSA PBS) containing live/dead Aqua (Life tech) at room temperature for 15 minutes. After washing the cells once in FAC buffer, a series of directly conjugated antibodies: anti-CD3 conjugated to BV605; Anti-CD25 conjugated to BV421; Anti-CD107a conjugated to FITC; Anti-EpCam conjugated to PE or anti-CD4 conjugated to PE; And anti-CD80 conjugated to PE/Cy5 or anti-HLA-DR conjugated to PE/Cy5. Samples of cells from each co-culture condition were also stained with the relevant isotype control antibody. All staining was performed in FAC buffer in a total volume of 50 μl/well at 15 min, 4°C. Thereafter, the cells were washed with FAC buffer (200 µl), resuspended in 200 µl of FAC buffer, and analyzed by flow cytometry (Attune).

Selective expression of CD80

Similar to the results described in Example 14, CD80 expression was detectable on the surface of more than 80% of ^{NG-348 infected EpCam + A549 cells, not EnAd infected or uninfected control cells (FIG. 16 ).} In contrast, CD3 ⁺ T cells do not show detectable expression of CD80 on the cell surface, indicating that, at least under these experimental conditions, transgene expression is selective for tumor cells in co-culture.

T cell activation Marker Upregulation

Flow cytometric analysis of T cell activation was evaluated by expression of live, CD3 ⁺ , T cell activation markers CD25 and HLA-DR on single cells. These data show that both the number of T cells expressing CD25 (FIGS. 17A and 17B) and the average level of CD25 expression on the T cell surface (FIG. 17C) were compared with EnAd or uninfected controls, by NG-348 infected A549 cells. It was shown to be higher for cultured T cells. Specifically, there was no difference in T cell activation state when compared to the untreated control group with EnAd (26.9%±3.4% and 25.3±3.5% of T cells expressing CD25, respectively), but CD25 was simultaneously with NG-348. It was upregulated (83.2±1.5%) on most of the cultured cells. CD25 expression in CD4 and CD8 T cell subpopulations was also analyzed by gating ^{CD3 +} T cells based on the expression of CD4. This assay showed that the expression of CD25, as compared to the non-infected control group EnAd and, significantly upregulated in both CD4 ⁺ and CD4 ^_ T cell subpopulation in NG-348-treated co-cultures (Fig. 18).

In contrast to CD25, the number of cells expressing HLA-DR was as low as less than 5% for all conditions tested (FIG. 19A ). This is probably due to an early point in time after co-culture where flow cytometric analysis is performed. However, compared to the control, there was a slight but significant increase in the mean fluorescence intensity of ^{HLA-DR stained CD3 +} HLA-DR ⁺ cells from NG-348 treated co-culture (FIG. 19B ).

T cells Degranulated stimulus

When A549 cells are infected with NG-348 (8.3%±1.7% of cells) compared to EnAd (0.6%±0.2% of cells) or untreated control (0.1%±0.02% of cells), Analysis of CD107a expression on the surface of live, CD3 ⁺ T cells showed a significant increase in the number of T cells, degranulated and thus stained with CD107a (FIG. 20 ). CD25 compared similarly to the up-regulation, and CD4 ⁺ T cells and CD4 ^_ Both sub-groups, or A549 EnAd control group showed a significant increase CD107a expression (Fig. 21).

IL-2, a stimulating cytokine, and IFNγ secretion

For detection of IL-2 or IFNγ expression, the co-culture supernatant is diluted with 5% BSA/PBS assay buffer (range 1:100 to 1:1000) and ELISA is human IL-2 ready set according to the manufacturer's protocol. It was performed using the Ready Set go Kit (Affymetrix) or the human IFN Gamma Ready Set Go Kit (Affymetrix).

The concentration of secreted IFNγ was determined by extrapolation from the standard curve. Expression of IL-2 was detected only in the supernatant of the co-culture using NG-348 infected A549 cells, and was not detectable in EnAd or untreated controls (FIG. 22A ). Expression of IFNγ was also detected at very high levels (>300 ng/ml) in the supernatants of cocultures from NG-348 infected A549 cells, which were significantly higher than EnAd or untreated controls (FIG. 22B ).

Example 16. T cell activation of CD4 and CD8 T cells infected with NG-348 carcinoma Independently by cell line To be mediated Number have

A549 lung carcinoma cells infected or uninfected with NG-348 or EnAd virus particles were co-cultured with ^{CD4 +} T cells or CD8 ^{+ T cells isolated from human PBMC donors.} T cell activation was evaluated by secretion of the stimulating cytokine IFNγ into the culture supernatant.

A549 cells were seeded according to the method described in Example 14 and left uninfected or infected with NG-348 or EnAd virus particles. ^{48 hours post infection, CD4 +} T cells or CD8 ⁺ T cells isolated by negative selection from PBMC donors were added to the A549 cell monolayer at a ratio of 8 T cells to 1 tumor cell. After 16 hours of co-culture, the supernatant was harvested according to the method described in Example 14 and evaluated for IFNγ.

Expression of IFNγ on CD4 ⁺ T cells was detected only in the supernatant in co-cultures from NG-348 infected A549 cells and was not detectable in EnAd or untreated controls (FIG. 23A ). Expression of IFNγ on CD8 ⁺ T cells was detected at significantly higher levels for NG-348 infected A549 cells than for EnAd or untreated controls (FIG. 23B ), which resulted in activation of both CD8 and CD4 cells, resulting in tumor It is demonstrated that IFNγ can be secreted by NG-348 viral activity in the cell line.

Example 17. NG-347 infected carcinoma By cell line Mediated T cell activation

A549 lung carcinoma cells infected or uninfected with NG-347 or EnAd virus particles were co-cultured with T cells isolated from human PBMC donors. T cell activation was evaluated by analyzing cell surface activation markers (by flow cytometry) and secretion of stimulating cytokines that are IFNγ (by ELISA analysis of cell supernatant).

A549 cells were seeded in 12 well plates at a cell density of 5e5 cells/well. After the plate was incubated for 18 hours at 37° C., 5% CO ₂ , cells were infected with 10 EnAd or NG-347 virus particles (ppc) per cell or left uninfected. ^{24 hours post infection, CD3 +} T cells isolated by negative selection from PBMC (MAC) were added to the A549 cell monolayer at a ratio of 5 T cells to 1 tumor cell. After performing co-culture for 48 hours, cell supernatants were collected for ELISA analysis, and tumor cells and T cells were harvested for flow cytometric analysis according to the method described in FIG. 15.

Harvested cells were stained with directly conjugated antibodies: anti-CD3 conjugated to BV605 and anti-CD69 conjugated to BV421. Samples of cells from each co-culture condition were also stained with the relevant isotype control antibody. All staining was performed in FAC buffer in a total volume of 50 μl/well at 15 min, 4°C. Thereafter, the cells were washed with FAC buffer (200 µl), resuspended in 200 µl of FAC buffer, and analyzed by flow cytometry (Attune).

CD69 T cell activation Marker Upregulation

Flow cytometric analysis of T cell activation was evaluated by expression of the T cell activation marker CD69 on live, CD3 ^{+, single cells.} This data showed that the number of T cells expressing CD69 was significantly higher in NG-347 infected A549 cells and cultured T cells than in EnAd or uninfected controls (FIG. 24 ).

Irritating cytokine IFNγ secretion

For detection of IL-2 or IFNγ expression, the co-culture supernatant was diluted with 5% BSA/PBS assay buffer (range 1:100 to 1:1000) and ELISA was subjected to human IFN gamma ready set high according to the manufacturer's protocol. This was done using the kit (Affymetrix).

The concentration of secreted IFNγ was determined by extrapolation from the standard curve. Expression of IFNγ was detected only in the supernatant of the co-culture using NG-347 infected A549 cells, and was not detectable in EnAd or untreated controls (FIG. 25 ).

Example 18: ε chain of the T cell activating antigen CD80 and human CD3 complex ( CD3ε ) Just pinned to Short chain Fv Expressing a fragment antibody EnAd Manufacture of virus

Using the plasmid pEnAd2.4, direct insertion of a cassette encoding the human T cell activating antigen CD80 (SEQ ID NO: 11) and the membrane-immobilized chimeric form of the single chain Fv anti-human CD3e with a C-terminal V5 tag (SEQ ID NO: 99) Plasmid pNG-348A was generated by this. The pNG-348 cassette contains a 5'short splice acceptor sequence (SEQ ID NO: 2); Membrane immobilized anti-human CD3e ScFv cDNA; C-terminal V5 tag (SEQ ID NO: 100); High efficiency self-cleavable P2A peptide sequence (SEQ ID NO: 7); It contains a human CD80 cDNA sequence and a 3'polyadenylation sequence (SEQ ID NO: 5). An illustration of the NG-348A transgene cassette is shown in Figure 26A. Construction of the plasmid was confirmed by DNA sequencing.

Virus manufacturing and identification

Plasmid pNG-348A was linearized by restriction digestion with the enzyme AscI to generate viral genome NG-348A (SEQ ID NO: 101). Virus NG-348A was amplified and purified according to the method described in Example 1.

Example 19: ε chain of human CD3 complex ( CD3ε ) Just pinned to Short chain Fv Expressing a fragment antibody EnAd Manufacture of virus

Using plasmid pEnAd2.4, by direct insertion of a cassette encoding a membrane-immobilized chimeric form of a short chain Fv anti-human CD3e with a C-terminal V5 tag (SEQ ID NO: 99) or without a V5 tag (SEQ ID NO: 15). Plasmids pNG-420 and pNG-420A were generated. The pNG-420 cassette contains the 5'short splice acceptor sequence CAGG; It contains a membrane immobilized anti-human CD3e scFv cDNA and a 3'polyadenylation sequence (SEQ ID NO: 5). The pNG-420A cassette contains the 5'short splice acceptor sequence cagg; Membrane immobilized anti-human CD3e ScFv cDNA; It contains a C-terminal V5 tag (SEQ ID NO: 100) and a 3'polyadenylation sequence (SEQ ID NO: 5). An illustration of the NG-420 and NG-420A transgene cassettes is shown in Figures 26B and 26C. Construction of the plasmid was confirmed by DNA sequencing.

Virus manufacturing and identification

Plasmids pNG-420 and pNG-420A were linearized by restriction digestion with the enzyme AscI to generate viral genomes NG-420 (SEQ ID NO: 102) and NG-420A (SEQ ID NO: 103). Viruses NG-420 and NG-420A were amplified and purified according to the method described in Example 1.

Example 20

A549 human lung carcinoma cells and MRC5 human fibroblast cells were incubated with EnAd, NG-347 or NG-348 virus (at 10 ppc) to compare viral genome replication, viral hexon and transgene expression by this cell type. After 72 hours incubation, cells were stained for FACS analysis of surface markers or supernatant, and cell lysates were prepared for viral genome replication (qPCR) or mRNA (RT-qPCR) analysis of hexon or transgene expression.

Viral genome replication and hexon mRNA expression for the two transgene-bearing viruses, NG-347 and NG-348, were equivalent to that for the parent virus, EnAd (FIG. 27 ). In the case of NG-348 (FIG. 28 ), CD80 and anti-human CD3-scFv transgene mRNA expression levels were high by A549 tumor cells and only low level signals for non-tumor MRC5 cells. CD80 protein expression on the surface of cells as assessed by FACS was detected in most NG-348 treated A549 cells, but not detectable in MRC5 cells, and CD80 was detected in cell types that remained untreated or treated with EnAd. Didn't. Similarly, CD80 transgene mRNA and protein expression after NG-347 treatment was selectively detected in A549 tumor cells rather than MRC5 cells (FIG. 29 ).

For EnAd and NG-347 treated cell cultures, the levels of MIP1α and IFNα mRNA in cell lysates and secreted proteins in the supernatant were measured by RT-qPCR and specific ELISA, respectively. Data (FIG. 30) showed selective expression of both transgenes by A549 tumor cells, without detectable MIP1α chemokine or IFNα cytokine in MRC5 supernatant.

Example 21

The isolated CD3 ⁺ T cells were cultured with 500 ppc or 5000 ppc of each virus for 3 days to evaluate the selectivity/activity of EnAd, NG-347 and NG-348 viruses by human T cells. Flow cytometric analysis of stained T cells with antibody targeting CD69, CD4, CD80, CD25 and CD3, b) ELISA analysis of human MIP1α, IFNα and IFNγ protein secretion, c) Selectivity/activity was evaluated by qPCR analysis of viral replication and d) RT-qPCR analysis of gene expression.

As shown in Figure 31, T cells did not support viral genome replication for any virus tested by the only background signal in the viral Hexon RT-qPCR assay. A549 tumor cells supported high levels of hexon mRNA expression. RT-qPCR analysis of transgene mRNA expression by T cells was performed despite the only background signal (less than 1 copy/cell) for CD80 by both NG-347 and NG-348, and high viral exposure (5000 ppc). It showed a similar lack of significant expression of anti-CD3-ScFv mRNA by NG-348. High levels of expression of both transgenes were detected by treated (10 ppc) A549 tumor cells (FIGS. 32 and 33 ). Expression of IFNα and MIP1α transgene mRNA was also selectively detected not by T cells treated with 5000 ppc, but also by NG-347 treated A549 tumor cells (at 10 ppc) (not EnAd) (FIG. 34 ). In addition, CD80 cell surface protein expression was detectable only by A549 cells, not T cells, for both NG-347 and NG-348 (FIGS. 32 and 33 ). EnAd treatment did not generate CD80 expression by either cell type, and A549 cell death (as assessed by dye uptake) was similarly high for all three viruses; Low levels of non-specific T cell death were induced by all viruses due to the very high levels of viral particles used in the experiment (FIGS. 32 and 33). Similar transgene mRNA and protein expression data were obtained when virus was used at 500 ppc (data not shown).

In the absence of tumor cells, human T cells purified to upregulate the activation markers CD25 or CD69 when incubated with any virus were not activated (Table 5).

Example 22

Virus selectivity experiments similar to those described in Example 21, including making the same activity assessment, were performed using non-isolated human PBMCs rather than purified T cells. As with human T cells in Example 21, the data from this study collectively demonstrate the lack of viral replication and transgene expression by human PBMCs. Figures 35-37 show data using 5000 ppc of EnAd, NG-347 or NG-348, but similar data was generated using 500 ppc (not shown). Fig. 35 shows viral genome replication and hexon mRNA expression, and Figs. 36 and 37 show transgene mRNA expression. The assay background was set according to the signal generated in the assay with each virus spiked with culture medium and then treated in the same manner as for the cell lysate sample. There was no detectable expression of the CD80 transgene on CD3+ T cells or CD40+ cells (mainly B cells) in this PBMC culture with any virus (not shown).

NG-347 and NG-348 virus particle mediated activation of innate immune cells (monocytes, DC) in PBMC cultures, downregulation of CD14 expression and upregulation of HLA-DR and endogenous cell surface CD80, and secretion of MIP1α and IFNα For, as shown in Figures 38 and 39, it was similar to that of EnAd (despite NG-347, which encodes both of these molecules in its genome, for EnAd and NG-348 that did not encode the transgene. It is noted that there was no increase in manufacturing level compared to that).

Example 23

This Example is similar in design to the experiments in Examples 15-17, 21 and 22, but in this study, human PBMC or purified T cells were simultaneously treated with virus pretreated (48 hours) A549 tumor cells or MRC5 fibroblasts. Cultured. A549 or MRC5 cells were treated with 10 ppc of EnAd, NG-347, NG-348 or left untreated (UTC) and cultured for 48 hours to allow sufficient time for viral replication and any transgene expression. Thereafter, PBMC or T cells were added to the culture and allowed to stand for 24 or 48 hours to evaluate the ability of virus-treated cells to activate T cells.

Figure 40 shows viral genomic replication data showing comparable replication of three viruses in PBMC or T cell co-culture with both cell types, the level of replication high with A549 tumor cells and low with MRC5 fibroblasts.

T cell activation as measured by upregulation of CD25 surface expression, and CD8 effector T cell downregulation as measured by upregulation of CD107a on the cell surface, and IFNγ production measured by intracellular cytokine staining , Compared to EnAd, all were selectively stimulated by NG-348 treated A549 cells, and there was no stimulation mediated by MRC co-culture (Table 6).

IFNγ secretion into the co-culture supernatant was also quantified by ELISA. The data (FIG. 41) similarly demonstrate the selective activation of T cells co-cultured with NG-348 treated A549 tumor cells and not MRC5 fibroblasts, by purified T cells or PBMCs used in the assay.

The ability of NG-347 to activate T cells was also evaluated by measuring the level of CD69 on T cells from purified T cells or co-cultures of PBMCs and A549 tumor cells or MRC5 fibroblasts. As shown in Table Z, a small increase in CD69 positive T cells was seen by NG-347 treatment of A549 tumor cells compared to EnAd, which itself caused upregulation of this early activation marker. This effect was not seen in the MRC5 co-culture. No CD80 expression was detected on T cells (not shown).

In a separate experiment, A549 cells treated with NG-347 and co-cultured with human CD3+ T cells resulted in upregulation of the CD69 activation marker on T cells and secretion of IFNγ (see FIGS. 24 and 25).

Example 24

CD14+ mononuclear cells were isolated from PBMCs by antibody-coated magnetic bead separation and incubated with human IL-4 and GM-CSF to differentiate them into dendritic cells. After 3 days of incubation, cells were treated with EnAd, NG-347 or NG-348 at 5000 ppc or left untreated. As a positive activation control, some cells were stimulated by LPS. After 2 days, supernatants were taken for cytokine ELISA, cells were stained for surface activation marker expression and analyzed by flow cytometry. As shown in Table 8, all viruses induce up-regulation of the costimulatory molecules CD80 and CD86, which were previously identified particle-mediated innate immune cells by transgene incorporation of NG-347 and NG-348 into the genome. Indicates that the activation effect does not change. All viruses also stimulated the secretion of similar levels of MIP1α and IFNα (Figure 42).

Example 25

In a series of experiments, JurkatDual cells were used in co-culture with tumor cells as a T cell activation reporter assay to evaluate the function of transgene expression by NG-347, NG-348 and NG-420 viruses, and EnAd was Serves as a negative control. JurkatDual cells stably express two different reporter genes: the NFκB reporter gene and the IFNa reactive secreted alkaline phosphatase (SEAP) reporter gene, which produces a secreted form of luciferase that is responsive to signaling through the T cell receptor complex. A549 cells were preincubated with virus at 10 ppc for 2 days, then JurkatDual cells were added for overnight co-culture (18-24 hours), and then supernatant was collected for assay of luciferase and SEAP activity. As shown in Fig. 43, NG-347 infected A549 cells selectively induce SEAP production (adjusted with production of IFNα) (see Fig. 11), but do not induce luciferase activity. In contrast, NG-348, which expresses the membrane anti-CD3-ScFv to activate the T cell receptor complex, induced luciferase rather than SEAP.

In another experiment, A549 lung carcinoma cells and HCT-116, HT-29 and DLD colon carcinoma cells were preincubated with 10 ppc of EnAd, NG-347, NG-348 or NG-420 virus for 48 hours, followed by overnight. The level of activation induced by co-culture with JurkatDual cells and testing the supernatant for the level of luciferase is indicated. As shown in Figure 44, all four tumor cell types incubated with NG-348 or NG-420 virus encoding cell surface anti-CD3-ScFv activated JurkatDual cells, but EnAd and NG-347 were uninfected. This was not due to the level of luciferase similar to that of the tumor cell control (UIC).

In another experiment, A549 or HT-29 tumor cells were pre-incubated with different amounts of NG-348 or NG-420, then JurkatDual cells were added and their luciferase secretion was measured. The data in Figure 45 showed that activation of NFκB activity in JurkatDual cells depends on the dose of virus used to treat tumor cells.

Example 26

Comparing the in vivo pharmacokinetics, biodistribution and particle-mediated systemic cytokine-inducing activity of EnAd and NG-348 after IV dosing in immunocompetent CD1 mice, and intravenous administration with ^{5x10 9 particles of EnAd or NG-348 in mice} And blood was killed at 2 minutes, 10 minutes, 30 minutes, 60 minutes and 120 minutes after dosing. Whole blood was DNA extracted and analyzed by qPCR for the level of the viral genome (FIG. 46 ). The clearance rates of both viruses from the blood followed similar kinetics. Similarly, like tissue biodistribution patterns, the induction of MCP-1 cytokine responses (a measure of particle mediated activation of innate immunity, such as liver Kupffer cells) was also similar for both viruses (FIG. 46 ).

Example 27

If the tumor is greater than 70 mm 3, HCT116 cells are implanted subcutaneously into CB17 SCID mice, and either by EnAd, NG-347 or NG-348 virus (5×10 ⁹ virus particles), or intratumoral (IT) or intravenous ( IV) Injected. For IV dosed mice, blood samples were taken from 3 mice from each group at 3, 15 and 30 minutes after IV dose, DNA was extracted and the level of viral genome in the blood was assessed by qPCR. (Pharmacokinetics [PK] analysis). The data (Figure 47) showed that NG-347 and NG-348 had similar PKs to EnAd (and to each other). After 6 hours, tumor, liver, lung and spleen were excised from 3 mice from each group. The homogenized tissue was DNA extracted and analyzed for the level of the viral genome by qPCR (biodistribution analysis). The data (Figure 48A) showed similar tissue biodistribution for the three viruses. After 7 days or 14-21 days, tumors were excised and homogenized from 3 mice from each group to generate tumor lysates, which were used to prepare both DNA and RNA. The level of the viral genome in the tumor was measured at two time points by qPCR analysis of the extracted DNA. The data (Figure 48B) shows that tumors from both IV and IT dosed mice have a higher level of viral genome than the amount of virus dosed, indicating viral replication in tissues, and IT dosing on day 7 Gave higher genomic levels than IV, but both were similarly high in the 14-21 day period. All three viruses replicated at similar levels.

Similarly, the levels of viral hexon mRNA in tumor lysates detected by RT-qPCR were comparable between EnAd, NG-347 and NG-348 at both time points tested (FIGS. 49 and 50 ). Similar levels of anti-CD3-ScFv and CD80 mRNA were detected at both dosing and time points for NG-348 treatment, as the only assay background read by EnAd dosing (FIGS. 50 and 51 ). MIP1α and IFNα mRNA levels were also selectively detected after NG-347 dosing (either IT or IV) (FIG. 52 ).

A specific ELISA was used to measure the level of the CD80 protein encoded by both NG-347 and NG-348, and the MIP1a protein encoded by NG-347 in tumor lysates. The data in FIG. 53 showed that after a single IV virus dosing, both proteins can also be selectively detected in tumor extracts. No protein was detected in blood samples from the same mouse.

Example 28

To assess the activity and tumor cell dependence of NG-348 virus in vivo, either human PBMC (5x10 ⁷ cells), A549 human tumor cells (5x10 ⁶ ) and EnAd (at 5x10 ⁹ ppc) or NG-348 A different combination of was injected into the peritoneum of immunodeficient SCID-beige mice, and the virus or control (saline) was dosed within 15 minutes after injection of the cells. After 3 days, the peritoneal cavity was washed with 5 ml of saline, and the recovered cells were analyzed by flow cytometric analysis by a series of T cell activation markers (CD25, CD69 and HLA-DR) after gating in the CD3+ T cell population. The level of T cell activation was evaluated. Data from two separate experiments (Table 9) demonstrate that NG-348 selectively generates human T cell activation in vivo in a tumor cell dependent manner.

SEQUENCE LISTING <110> PSIOXUS THERAPEUTICS LIMITED <120> ONCOLYTIC ADENOVIRUS ENCODING A B7 PROTEIN <130> WO2016/174200 <140> PCT/EP2016/059609 <141> 2016-04-29 <150> GB1507419.8 <151> 2015-04-30 <150> GB1516936.0 <151> 2015-09-24 <150> GB1522013.0 <151> 2015-12-14 <160> 109 <170> PatentIn version 3.5 <210> 1 <211> 35 <212> DNA <213> Artificial Sequence <220> <223> By DNA sequence corresponding to and including bp 29345-29379 of the EnAd genome. <400> 1 caaataaagt ttaacttgtt tatttgaaaa tcaat 35 <210> 2 <211> 48 <212> PRT <213> Artificial Sequence <220> <223> PDGF TM domain <400> 2 Ala Val Gly Gln Asp Thr Gln Glu Val Ile Val Val Pro His Ser Leu 1 5 10 15 Pro Phe Lys Val Val Val Ile Ser Ala Ile Leu Ala Leu Val Val Leu 20 25 30 Thr Ile Ile Ser Leu Ile Ile Leu Ile Met Leu Trp Gln Lys Pro Arg 35 40 45 <210> 3 <211> 14 <212> DNA <213> Artificial Sequence <220> <223> SPLICE ACCEPTOR SEQUENCE <400> 3 tttctctctt cagg 14 <210> 4 <211> 26 <212> DNA <213> Artificial Sequence <220> <223> SPLICE ACCEPTOR SEQUENCE <400> 4 tgctaatctt cctttctctc ttcagg 26 <210> 5 <211> 192 <212> DNA <213> Artificial Sequence <220> <223> poly adenylation sequence (SV40 late polyA sequence) <400> 5 cagacatgat aagatacatt gatgagtttg gacaaaccac aactagaatg cagtgaaaaa 60 aatgctttat ttgtgaaatt tgtgatgcta ttgctttatt tgtaaccatt ataagctgca 120 ataaacaagt taacaacaac aattgcattc attttatgtt tcaggttcag ggggaggtgt 180 gggaggtttt tt 192 <210> 6 <211> 551 <212> DNA <213> Artificial Sequence <220> <223> Internal Ribosome Entry Sequence (IRES) <400> 6 cgttactggc cgaagccgct tggaataagg ccggtgtgcg tttgtctata tgttattttc 60 caccatattg ccgtcttttg gcaatgtgag ggcccggaaa cctggccctg tcttcttgac 120 gagcattcct aggggtcttt cccctctcgc caaaggaatg caaggtctgt tgaatgtcgt 180 gaaggaagca gttcctctgg aagcttcttg aagacaaaca acgtctgtag cgaccctttg 240 caggcagcgg aaccccccac ctggcgacag gtgcctctgc ggccaaaagc cacgtgtata 300 agatacacct gcaaaggcgg cacaacccca gtgccacgtt gtgagttgga tagttgtgga 360 aagagtcaaa tggctcccct caagcgtatt caacaagggg ctgaaggatg cccagaaggt 420 accccattgt atgggatctg atctggggcc tcggtgcaca tgcttttcat gtgtttagtc 480 gaggttaaaa aacgtctagg ccccccgaac cacggggacg tggttttcct ttgaaaaaca 540 cgatgataat a 551 <210> 7 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> High efficiency self-cleavable P2A peptide sequence <400> 7 Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val 1 5 10 15 Glu Glu Asn Pro Gly Pro 20 <210> 8 <211> 21 <212> PRT <213> Artificial Sequence <220> <223> High efficiency self-cleavable F2A peptide sequence <400> 8 Gly Ser Gly Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu 1 5 10 15 Glu Asn Pro Gly Pro 20 <210> 9 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> High efficiency self-cleavable E2A peptide sequence <400> 9 Gly Ser Gly Gln Cys Thr Asn Tyr Ala Leu Leu Lys Leu Ala Gly Asp 1 5 10 15 Val Glu Ser Asn Pro Gly Pro 20 <210> 10 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> High efficiency self-cleavable T2A peptide sequence <400> 10 Gly Ser Gly Val Lys Gln Thr Leu Asn Phe Asp Leu Leu Lys Leu Ala 1 5 10 15 Gly Asp Val Glu Ser Asn Pro Gly Pro 20 25 <210> 11 <211> 288 <212> PRT <213> Artificial Sequence <220> <223> Human CD80 amino acid sequence <400> 11 Met Gly His Thr Arg Arg Gln Gly Thr Ser Pro Ser Lys Cys Pro Tyr 1 5 10 15 Leu Asn Phe Phe Gln Leu Leu Val Leu Ala Gly Leu Ser His Phe Cys 20 25 30 Ser Gly Val Ile His Val Thr Lys Glu Val Lys Glu Val Ala Thr Leu 35 40 45 Ser Cys Gly His Asn Val Ser Val Glu Glu Leu Ala Gln Thr Arg Ile 50 55 60 Tyr Trp Gln Lys Glu Lys Lys Met Val Leu Thr Met Met Ser Gly Asp 65 70 75 80 Met Asn Ile Trp Pro Glu Tyr Lys Asn Arg Thr Ile Phe Asp Ile Thr 85 90 95 Asn Asn Leu Ser Ile Val Ile Leu Ala Leu Arg Pro Ser Asp Glu Gly 100 105 110 Thr Tyr Glu Cys Val Val Leu Lys Tyr Glu Lys Asp Ala Phe Lys Arg 115 120 125 Glu His Leu Ala Glu Val Thr Leu Ser Val Lys Ala Asp Phe Pro Thr 130 135 140 Pro Ser Ile Ser Asp Phe Glu Ile Pro Thr Ser Asn Ile Arg Arg Ile 145 150 155 160 Ile Cys Ser Thr Ser Gly Gly Phe Pro Glu Pro His Leu Ser Trp Leu 165 170 175 Glu Asn Gly Glu Glu Leu Asn Ala Ile Asn Thr Thr Val Ser Gln Asp 180 185 190 Pro Glu Thr Glu Leu Tyr Ala Val Ser Ser Lys Leu Asp Phe Asn Met 195 200 205 Thr Thr Asn His Ser Phe Met Cys Leu Ile Lys Tyr Gly His Leu Arg 210 215 220 Val Asn Gln Thr Phe Asn Trp Asn Thr Thr Lys Gln Glu His Phe Pro 225 230 235 240 Asp Asn Leu Leu Pro Ser Trp Ala Ile Thr Leu Ile Ser Val Asn Gly 245 250 255 Ile Phe Val Ile Cys Cys Leu Thr Tyr Cys Phe Ala Pro Arg Cys Arg 260 265 270 Glu Arg Arg Arg Asn Glu Arg Leu Arg Arg Glu Ser Val Arg Pro Val 275 280 285 <210> 12 <211> 188 <212> PRT <213> Artificial Sequence <220> <223> Human Interferona amino acid sequence <400> 12 Met Ala Leu Thr Phe Ala Leu Leu Val Ala Leu Leu Val Leu Ser Cys 1 5 10 15 Lys Ser Ser Cys Ser Val Gly Cys Asp Leu Pro Gln Thr His Ser Leu 20 25 30 Gly Ser Arg Arg Thr Leu Met Leu Leu Ala Gln Met Arg Arg Ile Ser 35 40 45 Leu Phe Ser Cys Leu Lys Asp Arg His Asp Phe Gly Phe Pro Gln Glu 50 55 60 Glu Phe Gly Asn Gln Phe Gln Lys Ala Glu Thr Ile Pro Val Leu His 65 70 75 80 Glu Met Ile Gln Gln Ile Phe Asn Leu Phe Ser Thr Lys Asp Ser Ser 85 90 95 Ala Ala Trp Asp Glu Thr Leu Leu Asp Lys Phe Tyr Thr Glu Leu Tyr 100 105 110 Gln Gln Leu Asn Asp Leu Glu Ala Cys Val Ile Gln Gly Val Gly Val 115 120 125 Thr Glu Thr Pro Leu Met Lys Glu Asp Ser Ile Leu Ala Val Arg Lys 130 135 140 Tyr Phe Gln Arg Ile Thr Leu Tyr Leu Lys Glu Lys Lys Tyr Ser Pro 145 150 155 160 Cys Ala Trp Glu Val Val Arg Ala Glu Ile Met Arg Ser Phe Ser Leu 165 170 175 Ser Thr Asn Leu Gln Glu Ser Leu Arg Ser Lys Glu 180 185 <210> 13 <211> 179 <212> PRT <213> Artificial Sequence <220> <223> Human soluble Flt3 ligand amino acid sequence <400> 13 Met Thr Val Leu Ala Pro Ala Trp Ser Pro Thr Thr Tyr Leu Leu Leu 1 5 10 15 Leu Leu Leu Leu Ser Ser Gly Leu Ser Gly Thr Gln Asp Cys Ser Phe 20 25 30 Gln His Ser Pro Ile Ser Ser Asp Phe Ala Val Lys Ile Arg Glu Leu 35 40 45 Ser Asp Tyr Leu Leu Gln Asp Tyr Pro Val Thr Val Ala Ser Asn Leu 50 55 60 Gln Asp Glu Glu Leu Cys Gly Gly Leu Trp Arg Leu Val Leu Ala Gln 65 70 75 80 Arg Trp Met Glu Arg Leu Lys Thr Val Ala Gly Ser Lys Met Gln Gly 85 90 95 Leu Leu Glu Arg Val Asn Thr Glu Ile His Phe Val Thr Lys Cys Ala 100 105 110 Phe Gln Pro Pro Pro Ser Cys Leu Arg Phe Val Gln Thr Asn Ile Ser 115 120 125 Arg Leu Leu Gln Glu Thr Ser Glu Gln Leu Val Ala Leu Lys Pro Trp 130 135 140 Ile Thr Arg Gln Asn Phe Ser Arg Cys Leu Glu Leu Gln Cys Gln Pro 145 150 155 160 Asp Ser Ser Thr Leu Pro Pro Pro Trp Ser Pro Arg Pro Leu Glu Ala 165 170 175 Thr Ala Pro <210> 14 <211> 93 <212> PRT <213> Artificial Sequence <220> <223> Human Macrophage Inflammatory protein 1a amino acid sequence (LD78b isoform) <400> 14 Met Gln Val Ser Thr Ala Ala Leu Ala Val Leu Leu Cys Thr Met Ala 1 5 10 15 Leu Cys Asn Gln Val Leu Ser Ala Pro Leu Ala Ala Asp Thr Pro Thr 20 25 30 Ala Cys Cys Phe Ser Tyr Thr Ser Arg Gln Ile Pro Gln Asn Phe Ile 35 40 45 Ala Asp Tyr Phe Glu Thr Ser Ser Gln Cys Ser Lys Pro Ser Val Ile 50 55 60 Phe Leu Thr Lys Arg Gly Arg Gln Val Cys Ala Asp Pro Ser Glu Glu 65 70 75 80 Trp Val Gln Lys Tyr Val Ser Asp Leu Glu Leu Ser Ala 85 90 <210> 15 <211> 322 <212> PRT <213> Artificial Sequence <220> <223> Membrane anchored form of the anti-human CD3 single chain Fv <400> 15 Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly 1 5 10 15 Val His Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg 20 25 30 Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe 35 40 45 Thr Arg Tyr Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu 50 55 60 Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn 65 70 75 80 Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser 85 90 95 Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp 115 120 125 Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 130 135 140 Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser 145 150 155 160 Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys 165 170 175 Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Ser 180 185 190 Gly Thr Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser 195 200 205 Gly Val Pro Ala His Phe Arg Gly Ser Gly Ser Gly Thr Ser Tyr Ser 210 215 220 Leu Thr Ile Ser Gly Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys 225 230 235 240 Gln Gln Trp Ser Ser Asn Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu 245 250 255 Glu Ile Asn Arg Gly Ser Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu 260 265 270 Asn Ala Val Gly Gln Asp Thr Gln Glu Val Ile Val Val Pro His Ser 275 280 285 Leu Pro Phe Lys Val Val Val Ile Ser Ala Ile Leu Ala Leu Val Val 290 295 300 Leu Thr Ile Ile Ser Leu Ile Ile Leu Ile Met Leu Trp Gln Lys Lys 305 310 315 320 Pro Arg <210> 16 <211> 33493 <212> DNA <213> Artificial Sequence <220> <223> NG-330 virus genome sequence comprising the EnAd genome with a transgene cassette that encodes the T lymphocyte activation antigen, CD80, inserted in the region By. The transgene cassette contains a 5'SSA, human CD80 cDNA sequence and a 3'poly(A) <400> 16 tctatctata taatatacct tatagatgga atggtgccaa tatgtaaatg aggtgatttt 60 aaaaagtgtg gatcgtgtgg tgattggctg tggggttaac ggctaaaagg ggcggtgcga 120 ccgtgggaaa atgacgtttt gtgggggtgg agtttttttg caagttgtcg cgggaaatgt 180 gacgcataaa aaggcttttt tctcacggaa ctacttagtt ttcccacggt atttaacagg 240 aaatgaggta gttttgaccg gatgcaagtg aaaattgttg attttcgcgc gaaaactgaa 300 tgaggaagtg tttttctgaa taatgtggta tttatggcag ggtggagtat ttgttcaggg 360 ccaggtagac tttgacccat tacgtggagg tttcgattac cgtgtttttt acctgaattt 420 ccgcgtaccg tgtcaaagtc ttctgttttt acgtaggtgt cagctgatcg ctagggtatt 480 tatacctcag ggtttgtgtc aagaggccac tcttgagtgc cagcgagaag agttttctcc 540 tctgcgccgg cagtttaata ataaaaaaat gagagatttg cgatttctgc ctcaggaaat 600 aatctctgct gagactggaa atgaaatatt ggagcttgtg gtgcacgccc tgatgggaga 660 cgatccggag ccacctgtgc agctttttga gcctcctacg cttcaggaac tgtatgattt 720 agaggtagag ggatcggagg attctaatga ggaagctgta aatggctttt ttaccgattc 780 tatgctttta gctgctaatg aagggttaga attagatccg cctttggaca cttttgatac 840 tccaggggta attgtggaaa gcggtacagg tgtaagaaaa ttacctgatt tgagttccgt 900 ggactgtgat ttgcactgct atgaagacgg gtttcctccg agtgatgagg aggaccatga 960 aaaggagcag tccatgcaga ctgcagcggg tgagggagtg aaggctgcca atgttggttt 1020 tcagttggat tgcccggagc ttcctggaca tggctgtaag tcttgtgaat ttcacaggaa 1080 aaatactgga gtaaaggaac tgttatgttc gctttgttat atgagaacgc actgccactt 1140 tatttacagt aagtgtgttt aagttaaaat ttaaaggaat atgctgtttt tcacatgtat 1200 attgagtgtg agttttgtgc ttcttattat aggtcctgtg tctgatgctg atgaatcacc 1260 atctcctgat tctactacct cacctcctga gattcaagca cctgttcctg tggacgtgcg 1320 caagcccatt cctgtgaagc ttaagcctgg gaaacgtcca gcagtggaaa aacttgagga 1380 cttgttacag ggtggggacg gacctttgga cttgagtaca cggaaacgtc caagacaata 1440 agtgttccat atccgtgttt acttaaggtg acgtcaatat ttgtgtgaca gtgcaatgta 1500 ataaaaatat gttaactgtt cactggtttt tattgctttt tgggcgggga ctcaggtata 1560 taagtagaag cagacctgtg tggttagctc ataggagctg gctttcatcc atggaggttt 1620 gggccatttt ggaagacctt aggaagacta ggcaactgtt agagaacgct tcggacggag 1680 tctccggttt ttggagattc tggttcgcta gtgaattagc tagggtagtt tttaggataa 1740 aacaggacta taaacaagaa tttgaaaagt tgttggtaga ttgcccagga ctttttgaag 1800 ctcttaattt gggccatcag gttcacttta aagaaaaagt tttatcagtt ttagactttt 1860 caaccccagg tagaactgct gctgctgtgg cttttcttac ttttatatta gataaatgga 1920 tcccgcagac tcatttcagc aggggatacg ttttggattt catagccaca gcattgtgga 1980 gaacatggaa ggttcgcaag atgaggacaa tcttaggtta ctggccagtg cagcctttgg 2040 gtgtagcggg aatcctgagg catccaccgg tcatgccagc ggttctggag gaggaacagc 2100 aagaggacaa cccgagagcc ggcctggacc ctccagtgga ggaggcggag tagctgactt 2160 gtctcctgaa ctgcaacggg tgcttactgg atctacgtcc actggacggg ataggggcgt 2220 taagagggag agggcatcta gtggtactga tgctagatct gagttggctt taagtttaat 2280 gagtcgcaga cgtcctgaaa ccatttggtg gcatgaggtt cagaaagagg gaagggatga 2340 agtttctgta ttgcaggaga aatattcact ggaacaggtg aaaacatgtt ggttggagcc 2400 tgaggatgat tgggaggtgg ccattaaaaa ttatgccaag atagctttga ggcctgataa 2460 acagtataag attactagac ggattaatat ccggaatgct tgttacatat ctggaaatgg 2520 ggctgaggtg gtaatagata ctcaagacaa ggcagttatt agatgctgca tgatggatat 2580 gtggcctggg gtagtcggta tggaagcagt aacttttgta aatgttaagt ttaggggaga 2640 tggttataat ggaatagtgt ttatggccaa taccaaactt atattgcatg gttgtagctt 2700 ttttggtttc aacaatacct gtgtagatgc ctggggacag gttagtgtac ggggatgtag 2760 tttctatgcg tgttggattg ccacagctgg cagaaccaag agtcaattgt ctctgaagaa 2820 atgcatattt caaagatgta acctgggcat tctgaatgaa ggcgaagcaa gggtccgcca 2880 ctgcgcttct acagatactg gatgttttat tttgattaag ggaaatgcca gcgtaaagca 2940 taacatgatt tgcggtgctt ccgatgagag gccttatcaa atgctcactt gtgctggtgg 3000 gcattgtaat atgctggcta ctgtgcatat tgtttcccat caacgcaaaa aatggcctgt 3060 ttttgatcac aatgtgatga cgaagtgtac catgcatgca ggtgggcgta gaggaatgtt 3120 tatgccttac cagtgtaaca tgaatcatgt gaaagtgttg ttggaaccag atgccttttc 3180 cagaatgagc ctaacaggaa tttttgacat gaacatgcaa atctggaaga tcctgaggta 3240 tgatgatacg agatcgaggg tacgcgcatg cgaatgcgga ggcaagcatg ccaggttcca 3300 gccggtgtgt gtagatgtga ctgaagatct cagaccggat catttggtta ttgcccgcac 3360 tggagcagag ttcggatcca gtggagaaga aactgactaa ggtgagtatt gggaaaactt 3420 tggggtggga ttttcagatg gacagattga gtaaaaattt gttttttctg tcttgcagct 3480 gtcatgagtg gaaacgcttc ttttaagggg ggagtcttca gcccttatct gacagggcgt 3540 ctcccatcct gggcaggagt tcgtcagaat gttatgggat ctactgtgga tggaagaccc 3600 gtccaacccg ccaattcttc aacgctgacc tatgctactt taagttcttc acctttggac 3660 gcagctgcag ctgccgccgc cgcttctgtt gccgctaaca ctgtgcttgg aatgggttac 3720 tatggaagca tcatggctaa ttccacttcc tctaataacc cttctaccct gactcaggac 3780 aagttacttg tccttttggc ccagctggag gctttgaccc aacgtctggg tgaactttct 3840 cagcaggtgg tcgagttgcg agtacaaact gagtctgctg tcggcacggc aaagtctaaa 3900 taaaaaaatc ccagaatcaa tgaataaata aacaagcttg ttgttgattt aaaatcaagt 3960 gtttttattt catttttcgc gcacggtatg ccctagacca ccgatctcta tcattgagaa 4020 ctcggtggat tttttccagg atcctataga ggtgggattg aatgtttaga tacatgggca 4080 ttaggccgtc tttggggtgg agatagctcc attgaaggga ttcatgctcc ggggtagtgt 4140 tgtaaatcac ccagtcataa caaggtcgca gtgcatggtg ttgcacaata tcttttagaa 4200 gtaggctgat tgccacagat aagcccttgg tgtaggtgtt tacaaaccgg ttgagctggg 4260 atgggtgcat tcggggtgaa attatgtgca ttttggattg gatttttaag ttggcaatat 4320 tgccgccaag atcccgtctt gggttcatgt tatgaaggac caccaagacg gtgtatccgg 4380 tacatttagg aaatttatcg tgcagcttgg atggaaaagc gtggaaaaat ttggagacac 4440 ccttgtgtcc tccaagattt tccatgcact catccatgat aatagcaatg gggccgtggg 4500 cagcggcgcg ggcaaacacg ttccgtgggt ctgacacatc atagttatgt tcctgagtta 4560 aatcatcata agccatttta atgaatttgg ggcggagagt accagattgg ggtatgaatg 4620 ttccttcggg ccccggagca tagttcccct cacagatttg catttcccaa gctttcagtt 4680 ccgagggtgg aatcatgtcc acctgggggg ctatgaaaaa caccgtttct ggggcggggg 4740 tgattaattg tgatgatagc aaatttctga gcaattgaga tttgccacat ccggtggggc 4800 cataaatgat tccgattacg ggttgcaggt ggtagtttag ggaacggcaa ctgccgtctt 4860 ctcgaagcaa gggggccacc tcgttcatca tttcccttac atgcatattt tcccgcacca 4920 aatccattag gaggcgctct cctcctagtg atagaagttc ttgtagtgag gaaaagtttt 4980 tcagcggttt cagaccgtca gccatgggca ttttggagag agtttgctgc aaaagttcta 5040 gtctgttcca cagttcagtg atgtgttcta tggcatctcg atccagcaga cctcctcgtt 5100 tcgcgggttt ggacggctcc tggaataggg tatgagacga tgggcgtcca gcgctgccag 5160 ggttcggtcc ttccagggtc tcagtgttcg agtcagggtt gtttccgtca cagtgaaggg 5220 gtgtgcgcct gcttgggcgc ttgccagggt gcgcttcaga ctcatcctgc tggtcgaaaa 5280 cttctgtcgc ttggcgccct gtatgtcggc caagtagcag tttaccatga gttcgtagtt 5340 gagcgcctcg gctgcgtggc ctttggcgcg gagcttacct ttggaagttt tcttgcatac 5400 cgggcagtat aggcatttca gcgcatacaa cttgggcgca aggaaaacgg attctgggga 5460 gtatgcatct gcgccgcagg aggcgcaaac agtttcacat tccaccagcc aggttaaatc 5520 cggttcattg gggtcaaaaa caagttttcc gccatatttt ttgatgcgtt tcttaccttt 5580 ggtctccatg agttcgtgtc ctcgttgagt gacaaacagg ctgtccgtgt ccccgtagac 5640 tgattttaca ggcctcttct ccagtggagt gcctcggtct tcttcgtaca ggaactctga 5700 ccactctgat acaaaggcgc gcgtccaggc cagcacaaag gaggctatgt gggaggggta 5760 gcgatcgttg tcaaccaggg ggtccacctt ttccaaagta tgcaaacaca tgtcaccctc 5820 ttcaacatcc aggaatgtga ttggcttgta ggtgtatttc acgtgacctg gggtccccgc 5880 tgggggggta taaaaggggg cggttctttg ctcttcctca ctgtcttccg gatcgctgtc 5940 caggaacgtc agctgttggg gtaggtattc cctctcgaag gcgggcatga cctctgcact 6000 caggttgtca gtttctaaga acgaggagga tttgatattg acagtgccgg ttgagatgcc 6060 tttcatgagg ttttcgtcca tctggtcaga aaacacaatt tttttattgt caagtttggt 6120 ggcaaatgat ccatacaggg cgttggataa aagtttggca atggatcgca tggtttggtt 6180 cttttccttg tccgcgcgct ctttggcggc gatgttgagt tggacatact cgcgtgccag 6240 gcacttccat tcggggaaga tagttgttaa ttcatctggc acgattctca cttgccaccc 6300 tcgattatgc aaggtaatta aatccacact ggtggccacc tcgcctcgaa ggggttcatt 6360 ggtccaacag agcctacctc ctttcctaga acagaaaggg ggaagtgggt ctagcataag 6420 ttcatcggga gggtctgcat ccatggtaaa gattcccgga agtaaatcct tatcaaaata 6480 gctgatggga gtggggtcat ctaaggccat ttgccattct cgagctgcca gtgcgcgctc 6540 atatgggtta aggggactgc cccatggcat gggatgggtg agtgcagagg catacatgcc 6600 acagatgtca tagacgtaga tgggatcctc aaagatgcct atgtaggttg gatagcatcg 6660 cccccctctg atacttgctc gcacatagtc atatagttca tgtgatggcg ctagcagccc 6720 cggacccaag ttggtgcgat tgggtttttc tgttctgtag acgatctggc gaaagatggc 6780 gtgagaattg gaagagatgg tgggtctttg aaaaatgttg aaatgggcat gaggtagacc 6840 tacagagtct ctgacaaagt gggcataaga ttcttgaagc ttggttacca gttcggcggt 6900 gacaagtacg tctagggcgc agtagtcaag tgtttcttga atgatgtcat aacctggttg 6960 gtttttcttt tcccacagtt cgcggttgag aaggtattct tcgcgatcct tccagtactc 7020 ttctagcgga aacccgtctt tgtctgcacg gtaagatcct agcatgtaga actgattaac 7080 tgccttgtaa gggcagcagc ccttctctac gggtagagag tatgcttgag cagcttttcg 7140 tagcgaagcg tgagtaaggg caaaggtgtc tctgaccatg actttgagga attggtattt 7200 gaagtcgatg tcgtcacagg ctccctgttc ccagagttgg aagtctaccc gtttcttgta 7260 ggcggggttg ggcaaagcga aagtaacatc attgaagaga atcttgccgg ccctgggcat 7320 gaaattgcga gtgatgcgaa aaggctgtgg tacttccgct cggttattga taacctgggc 7380 agctaggacg atctcgtcga aaccgttgat gttgtgtcct acgatgtata attctatgaa 7440 acgcggcgtg cctctgacgt gaggtagctt actgagctca tcaaaggtta ggtctgtggg 7500 gtcagataag gcgtagtgtt cgagagccca ttcgtgcagg tgaggattcg ctttaaggaa 7560 ggaggaccag aggtccactg ccagtgctgt ttgtaactgg tcccggtact gacgaaaatg 7620 ccgtccgact gccatttttt ctggggtgac gcaatagaag gtttgggggt cctgccgcca 7680 gcgatcccac ttgagtttta tggcgaggtc ataggcgatg ttgacgagcc gctggtctcc 7740 agagagtttc atgaccagca tgaaggggat tagctgcttg ccaaaggacc ccatccaggt 7800 gtaggtttcc acatcgtagg tgagaaagag cctttctgtg cgaggatgag agccaatcgg 7860 gaagaactgg atctcctgcc accagttgga ggaatggctg ttgatgtgat ggaagtagaa 7920 ctccctgcga cgcgccgagc attcatgctt gtgcttgtac agacggccgc agtagtcgca 7980 gcgttgcacg ggttgtatct cgtgaatgag ttgtacctgg cttcccttga cgagaaattt 8040 cagtgggaag ccgaggcctg gcgattgtat ctcgtgcttt actatgttgt ctgcatcggc 8100 ctgttcatct tctgtctcga tggtggtcat gctgacgagc cctcgcggga ggcaagtcca 8160 gacctcggcg cggcaggggc ggagctcgag gacgagagcg cgcaggctgg agctgtccag 8220 ggtcctgaga cgctgcggac tcaggttagt aggcagtgtc aggagattaa cttgcatgat 8280 cttttggagg gcgtgcggga ggttcagata gtacttgatc tcaacgggtc cgttggtgga 8340 gatgtcgatg gcttgcaggg ttccgtgtcc cttgggcgct accaccgtgc ccttgttttt 8400 cattttggac ggcggtggct ctgttgcttc ttgcatgttt agaagcggtg tcgagggcgc 8460 gcaccgggcg gcaggggcgg ctcgggaccc ggcggcatgg ctggcagtgg tacgtcggcg 8520 ccgcgcgcgg gtaggttctg gtactgcgcc ctgagaagac tcgcatgcgc gacgacgcgg 8580 cggttgacat cctggatctg acgcctctgg gtgaaagcta ccggccccgt gagcttgaac 8640 ctgaaagaga gttcaacaga atcaatctcg gtatcgttga cggcggcttg cctaaggatt 8700 tcttgcacgt caccagagtt gtcctggtag gcgatctccg ccatgaactg ctcgatctct 8760 tcctcttgaa gatctccgcg gcccgctctc tcgacggtgg ccgcgaggtc gttggagatg 8820 cgcccaatga gttgagagaa tgcattcatg cccgcctcgt tccagacgcg gctgtagacc 8880 acggccccca cgggatctct cgcgcgcatg accacctggg cgaggttgag ctccacgtgg 8940 cgggtgaaga ccgcatagtt gcataggcgc tggaaaaggt agttgagtgt ggtggcgatg 9000 tgctcggtga cgaagaaata catgatccat cgtctcagcg gcatctcgct gacatcgccc 9060 agagcttcca agcgctccat ggcctcgtag aagtccacgg caaaattaaa aaactgggag 9120 tttcgcgcgg acacggtcaa ctcctcttcc agaagacgga taagttcggc gatggtggtg 9180 cgcacctcgc gctcgaaagc ccctgggatt tcttcctcaa tctcttcttc ttccactaac 9240 atctcttcct cttcaggtgg ggctgcagga ggagggggaa cgcggcgacg ccggcggcgc 9300 acgggcagac ggtcgatgaa tctttcaatg acctctccgc ggcggcggcg catggtttca 9360 gtgacggcgc ggccgttctc gcgcggtcgc agagtaaaaa caccgccgcg catctcctta 9420 aagtggtgac tgggaggttc tccgtttggg agggagaggg cgctgattat acattttatt 9480 aattggcccg tagggactgc acgcagagat ctgatcgtgt caagatccac gggatctgaa 9540 aacctttcga cgaaagcgtc taaccagtca cagtcacaag gtaggctgag tacggcttct 9600 tgtgggcggg ggtggttatg tgttcggtct gggtcttctg tttcttcttc atctcgggaa 9660 ggtgagacga tgctgctggt gatgaaatta aagtaggcag ttctaagacg gcggatggtg 9720 gcgaggagca ccaggtcttt gggtccggct tgctggatac gcaggcgatt ggccattccc 9780 caagcattat cctgacatct agcaagatct ttgtagtagt cttgcatgag ccgttctacg 9840 ggcacttctt cctcacccgt tctgccatgc atacgtgtga gtccaaatcc gcgcattggt 9900 tgtaccagtg ccaagtcagc tacgactctt tcggcgagga tggcttgctg tacttgggta 9960 agggtggctt gaaagtcatc aaaatccaca aagcggtggt aagctcctgt attaatggtg 10020 taagcacagt tggccatgac tgaccagtta actgtctggt gaccagggcg cacgagctcg 10080 gtgtatttaa ggcgcgaata ggcgcgggtg tcaaagatgt aatcgttgca ggtgcgcacc 10140 agatactggt accctataag aaaatgcggc ggtggttggc ggtagagagg ccatcgttct 10200 gtagctggag cgccaggggc gaggtcttcc aacataaggc ggtgatagcc gtagatgtac 10260 ctggacatcc aggtgattcc tgcggcggta gtagaagccc gaggaaactc gcgtacgcgg 10320 ttccaaatgt tgcgtagcgg catgaagtag ttcattgtag gcacggtttg accagtgagg 10380 cgcgcgcagt cattgatgct ctatagacac ggagaaaatg aaagcgttca gcgactcgac 10440 tccgtagcct ggaggaacgt gaacgggttg ggtcgcggtg taccccggtt cgagacttgt 10500 actcgagccg gccggagccg cggctaacgt ggtattggca ctcccgtctc gacccagcct 10560 acaaaaatcc aggatacgga atcgagtcgt tttgctggtt tccgaatggc agggaagtga 10620 gtcctatttt ttttttttgc cgctcagatg catcccgtgc tgcgacagat gcgcccccaa 10680 caacagcccc cctcgcagca gcagcagcag caatcacaaa aggctgtccc tgcaactact 10740 gcaactgccg ccgtgagcgg tgcgggacag cccgcctatg atctggactt ggaagagggc 10800 gaaggactgg cacgtctagg tgcgccttca cccgagcggc atccgcgagt tcaactgaaa 10860 aaagattctc gcgaggcgta tgtgccccaa cagaacctat ttagagacag aagcggcgag 10920 gagccggagg agatgcgagc ttcccgcttt aacgcgggtc gtgagctgcg tcacggtttg 10980 gaccgaagac gagtgttgcg ggacgaggat ttcgaagttg atgaaatgac agggatcagt 11040 cctgccaggg cacacgtggc tgcagccaac cttgtatcgg cttacgagca gacagtaaag 11 100 gaagagcgta acttccaaaa gtcttttaat aatcatgtgc gaaccctgat tgcccgcgaa 11160 gaagttaccc ttggtttgat gcatttgtgg gatttgatgg aagctatcat tcagaaccct 11220 actagcaaac ctctgaccgc ccagctgttt ctggtggtgc aacacagcag agacaatgag 11280 gctttcagag aggcgctgct gaacatcacc gaacccgagg ggagatggtt gtatgatctt 11340 atcaacattc tacagagtat catagtgcag gagcggagcc tgggcctggc cgagaaggtg 11400 gctgccatca attactcggt tttgagcttg ggaaaatatt acgctcgcaa aatctacaag 11460 actccatacg ttcccataga caaggaggtg aagatagatg ggttctacat gcgcatgacg 11520 ctcaaggtct tgaccctgag cgatgatctt ggggtgtatc gcaatgacag aatgcatcgc 11580 gcggttagcg ccagcaggag gcgcgagtta agcgacaggg aactgatgca cagtttgcaa 11640 agagctctga ctggagctgg aaccgagggt gagaattact tcgacatggg agctgacttg 11700 cagtggcagc ctagtcgcag ggctctgagc gccgcgacgg caggatgtga gcttccttac 11760 atagaagagg cggatgaagg cgaggaggaa gagggcgagt acttggaaga ctgatggcac 11820 aacccgtgtt ttttgctaga tggaacagca agcaccggat cccgcaatgc gggcggcgct 11880 gcagagccag ccgtccggca ttaactcctc ggacgattgg acccaggcca tgcaacgtat 11940 catggcgttg acgactcgca accccgaagc ctttagacag caaccccagg ccaaccgtct 12000 atcggccatc atggaagctg tagtgccttc ccgctctaat cccactcatg agaaggtcct 12060 ggccatcgtg aacgcgttgg tggagaacaa agctattcgt ccagatgagg ccggactggt 12120 atacaacgct ctcttagaac gcgtggctcg ctacaacagt agcaatgtgc aaaccaattt 12180 ggaccgtatg ataacagatg tacgcgaagc cgtgtctcag cgcgaaaggt tccagcgtga 12240 tgccaacctg ggttcgctgg tggcgttaaa tgctttcttg agtactcagc ctgctaatgt 12300 gccgcgtggt caacaggatt atactaactt tttaagtgct ttgagactga tggtatcaga 12360 agtacctcag agcgaagtgt atcagtccgg tcctgattac ttctttcaga ctagcagaca 12420 gggcttgcag acggtaaatc tgagccaagc ttttaaaaac cttaaaggtt tgtggggagt 12480 gcatgccccg gtaggagaaa gagcaaccgt gtctagcttg ttaactccga actcccgcct 12540 attattactg ttggtagctc ctttcaccga cagcggtagc atcgaccgta attcctattt 12600 gggttaccta ctaaacctgt atcgcgaagc catagggcaa agtcaggtgg acgagcagac 12660 ctatcaagaa attacccaag tcagtcgcgc tttgggacag gaagacactg gcagtttgga 12720 agccactctg aacttcttgc ttaccaatcg gtctcaaaag atccctcctc aatatgctct 12780 tactgcggag gaggagagga tccttagata tgtgcagcag agcgtgggat tgtttctgat 12840 gcaagagggg gcaactccga ctgcagcact ggacatgaca gcgcgaaata tggagcccag 12900 catgtatgcc agtaaccgac ctttcattaa caaactgctg gactacttgc acagagctgc 12960 cgctatgaac tctgattatt tcaccaatgc catcttaaac ccgcactggc tgcccccacc 13020 tggtttctac acgggcgaat atgacatgcc cgaccctaat gacggatttc tgtgggacga 13080 cgtggacagc gatgtttttt cacctctttc tgatcatcgc acgtggaaaa aggaaggcgg 13140 cgatagaatg cattcttctg catcgctgtc cggggtcatg ggtgctaccg cggctgagcc 13200 cgagtctgca agtccttttc ctagtctacc cttttctcta cacagtgtac gtagcagcga 13260 agtgggtaga ataagtcgcc cgagtttaat gggcgaagag gagtatctaa acgattcctt 13320 gctcagaccg gcaagagaaa aaaatttccc aaacaatgga atagaaagtt tggtggataa 13380 aatgagtaga tggaagactt atgctcagga tcacagagac gagcctggga tcatggggat 13440 tacaagtaga gcgagccgta gacgccagcg ccatgacaga cagaggggtc ttgtgtggga 13500 cgatgaggat tcggccgatg atagcagcgt gctggacttg ggtgggagag gaaggggcaa 13560 cccgtttgct catttgcgcc ctcgcttggg tggtatgttg taaaaaaaaa taaaaaaaaa 13620 actcaccaag gccatggcga cgagcgtacg ttcgttcttc tttattatct gtgtctagta 13680 taatgaggcg agtcgtgcta ggcggagcgg tggtgtatcc ggagggtcct cctccttcgt 13740 acgagagcgt gatgcagcag cagcaggcga cggcggtgat gcaatcccca ctggaggctc 13800 cctttgtgcc tccgcgatac ctggcaccta cggagggcag aaacagcatt cgttattcgg 13860 aactggcacc tcagtacgat accaccaggt tgtatctggt ggacaacaag tcggcggaca 13920 ttgcttctct gaactatcag aatgaccaca gcaacttctt gaccacggtg gtgcaaaaca 13980 atgactttac ccctacggaa gccagcaccc agaccattaa ctttgatgaa cgatcgcggt 14040 ggggcggtca gctaaagacc atcatgcata ctaacatgcc aaacgtgaac gagtatatgt 14100 ttagtaacaa gttcaaagcg cgtgtgatgg tgtccagaaa acctcccgac ggtgctgcag 14160 ttggggatac ttatgatcac aagcaggata ttttgaaata tgagtggttc gagtttactt 14220 tgccagaagg caacttttca gttactatga ctattgattt gatgaacaat gccatcatag 14280 ataattactt gaaagtgggt agacagaatg gagtgcttga aagtgacatt ggtgttaagt 14340 tcgacaccag gaacttcaag ctgggatggg atcccgaaac caagttgatc atgcctggag 14400 tgtatacgta tgaagccttc catcctgaca ttgtcttact gcctggctgc ggagtggatt 14460 ttaccgagag tcgtttgagc aaccttcttg gtatcagaaa aaaacagcca tttcaagagg 14520 gttttaagat tttgtatgaa gatttagaag gtggtaatat tccggccctc ttggatgtag 14580 atgcctatga gaacagtaag aaagaacaaa aagccaaaat agaagctgct acagctgctg 14640 cagaagctaa ggcaaacata gttgccagcg actctacaag ggttgctaac gctggagagg 14700 tcagaggaga caattttgcg ccaacacctg ttccgactgc agaatcatta ttggccgatg 14760 tgtctgaagg aacggacgtg aaactcacta ttcaacctgt agaaaaagat agtaagaata 14820 gaagctataa tgtgttggaa gacaaaatca acacagccta tcgcagttgg tatctttcgt 14880 acaattatgg cgatcccgaa aaaggagtgc gttcctggac attgctcacc acctcagatg 14940 tcacctgcgg agcagagcag gtctactggt cgcttccaga catgatgaag gatcctgtca 15000 ctttccgctc cactagacaa gtcagtaact accctgtggt gggtgcagag cttatgcccg 15060 tcttctcaaa gagcttctac aacgaacaag ctgtgtactc ccagcagctc cgccagtcca 15120 cctcgcttac gcacgtcttc aaccgctttc ctgagaacca gattttaatc cgtccgccgg 15180 cgcccaccat taccaccgtc agtgaaaacg ttcctgctct cacagatcac gggaccctgc 15240 cgttgcgcag cagtatccgg ggagtccaac gtgtgaccgt tactgacgcc agacgccgca 15300 cctgtcccta cgtgtacaag gcactgggca tagtcgcacc gcgcgtcctt tcaagccgca 15360 ctttctaaaa aaaaaaaaaa tgtccattct tatctcgccc agtaataaca ccggttgggg 15420 tctgcgcgct ccaagcaaga tgtacggagg cgcacgcaaa cgttctaccc aacatcctgt 15480 ccgtgttcgc ggacattttc gcgctccatg gggcgccctc aagggccgca ctcgcgttcg 15540 aaccaccgtc gatgatgtaa tcgatcaggt ggttgccgac gcccgtaatt atactcctac 15600 tgcgcctaca tctactgtgg atgcagttat tgacagtgta gtggctgacg ctcgcaacta 15660 tgctcgacgt aagagccggc gaaggcgcat tgccagacgc caccgagcta ccactgccat 15720 gcgagccgca agagctctgc tacgaagagc tagacgcgtg gggcgaagag ccatgcttag 15780 ggcggccaga cgtgcagctt cgggcgccag cgccggcagg tcccgcaggc aagcagccgc 15840 tgtcgcagcg gcgactattg ccgacatggc ccaatcgcga agaggcaatg tatactgggt 15900 gcgtgacgct gccaccggtc aacgtgtacc cgtgcgcacc cgtccccctc gcacttagaa 15960 gatactgagc agtctccgat gttgtgtccc agcggcgagg atgtccaagc gcaaatacaa 16020 ggaagaaatg ctgcaggtta tcgcacctga agtctacggc caaccgttga aggatgaaaa 16080 aaaaccccgc aaaatcaagc gggttaaaaa ggacaaaaaa gaagaggaag atggcgatga 16140 tgggctggcg gagtttgtgc gcgagtttgc cccacggcga cgcgtgcaat ggcgtgggcg 16200 caaagttcga catgtgttga gacctggaac ttcggtggtc tttacacccg gcgagcgttc 16260 aagcgctact tttaagcgtt cctatgatga ggtgtacggg gatgatgata ttcttgagca 16320 ggcggctgac cgattaggcg agtttgctta tggcaagcgt agtagaataa cttccaagga 16380 tgagacagtg tcgataccct tggatcatgg aaatcccacc cctagtctta aaccggtcac 16440 tttgcagcaa gtgttacccg taactccgcg aacaggtgtt aaacgcgaag gtgaagattt 16500 gtatcccact atgcaactga tggtacccaa acgccagaag ttggaggacg ttttggagaa 16560 agtaaaagtg gatccagata ttcaacctga ggttaaagtg agacccatta agcaggtagc 16620 gcctggtctg ggggtacaaa ctgtagacat taagattccc actgaaagta tggaagtgca 16680 aactgaaccc gcaaagccta ctgccacctc cactgaagtg caaacggatc catggatgcc 16740 catgcctatt acaactgacg ccgccggtcc cactcgaaga tcccgacgaa agtacggtcc 16800 agcaagtctg ttgatgccca attatgttgt acacccatct attattccta ctcctggtta 16860 ccgaggcact cgctactatc gcagccgaaa cagtacctcc cgccgtcgcc gcaagacacc 16920 tgcaaatcgc agtcgtcgcc gtagacgcac aagcaaaccg actcccggcg ccctggtgcg 16980 gcaagtgtac cgcaatggta gtgcggaacc tttgacactg ccgcgtgcgc gttaccatcc 17040 gagtatcatc acttaatcaa tgttgccgct gcctccttgc agatatggcc ctcacttgtc 17100 gccttcgcgt tcccatcact ggttaccgag gaagaaactc gcgccgtaga agagggatgt 17160 tgggacgcgg aatgcgacgc tacaggcgac ggcgtgctat ccgcaagcaa ttgcggggtg 17220 gttttttacc agccttaatt ccaattatcg ctgctgcaat tggcgcgata ccaggcatag 17280 cttccgtggc ggttcaggcc tcgcaacgac attgacattg gaaaaaaacg tataaataaa 17340 aaaaaaaaaa tacaatggac tctgacactc ctggtcctgt gactatgttt tcttagagat 17400 ggaagacatc aatttttcat ccttggctcc gcgacacggc acgaagccgt acatgggcac 17460 ctggagcgac atcggcacga gccaactgaa cgggggcgcc ttcaattgga gcagtatctg 17520 gagcgggctt aaaaattttg gctcaaccat aaaaacatac gggaacaaag cttggaacag 17580 cagtacagga caggcgctta gaaataaact taaagaccag aacttccaac aaaaagtagt 17640 cgatgggata gcttccggca tcaatggagt ggtagatttg gctaaccagg ctgtgcagaa 17700 aaagataaac agtcgtttgg acccgccgcc agcaacccca ggtgaaatgc aagtggagga 17760 agaaattcct ccgccagaaa aacgaggcga caagcgtccg cgtcccgatt tggaagagac 17820 gctggtgacg cgcgtagatg aaccgccttc ttatgaggaa gcaacgaagc ttggaatgcc 17880 caccactaga ccgatagccc caatggccac cggggtgatg aaaccttctc agttgcatcg 17940 acccgtcacc ttggatttgc cccctccccc tgctgctact gctgtacccg cttctaagcc 18000 tgtcgctgcc ccgaaaccag tcgccgtagc caggtcacgt cccgggggcg ctcctcgtcc 18060 aaatgcgcac tggcaaaata ctctgaacag catcgtgggt ctaggcgtgc aaagtgtaaa 18 120 acgccgtcgc tgcttttaat taaatatgga gtagcgctta acttgcctat ctgtgtatat 18180 gtgtcattac acgccgtcac agcagcagag gaaaaaagga agaggtcgtg cgtcgacgct 18240 gagttacttt caagatggcc accccatcga tgctgcccca atgggcatac atgcacatcg 18300 ccggacagga tgcttcggag tacctgagtc cgggtctggt gcagttcgcc cgcgccacag 18360 acacctactt caatctggga aataagttta gaaatcccac cgtagcgccg acccacgatg 18420 tgaccaccga ccgtagccag cggctcatgt tgcgcttcgt gcccgttgac cgggaggaca 18480 atacatactc ttacaaagtg cggtacaccc tggccgtggg cgacaacaga gtgctggata 18540 tggccagcac gttctttgac attaggggtg tgttggacag aggtcccagt ttcaaaccct 18600 attctggtac ggcttacaac tccctggctc ctaaaggcgc tccaaataca tctcagtgga 18660 ttgcagaagg tgtaaaaaat acaactggtg aggaacacgt aacagaagag gaaaccaata 18720 ctactactta cacttttggc aatgctcctg taaaagctga agctgaaatt acaaaagaag 18780 gactcccagt aggtttggaa gtttcagatg aagaaagtaa accgatttat gctgataaaa 18840 catatcagcc agaacctcag ctgggagatg aaacttggac tgaccttgat ggaaaaaccg 18900 aaaagtatgg aggcagggct ctcaaacccg atactaagat gaaaccatgc tacgggtcct 18960 ttgccaaacc tactaatgtg aaaggcggtc aggcaaaaca aaaaacaacg gagcagccaa 19020 atcagaaagt cgaatatgat atcgacatgg agttttttga tgcggcatcg cagaaaacaa 19080 acttaagtcc taaaattgtc atgtatgcag aaaatgtaaa tttggaaact ccagacactc 19140 atgtagtgta caaacctgga acagaagaca caagttccga agctaatttg ggacaacaat 19200 ctatgcccaa cagacccaac tacattggct tcagagataa ctttattgga cttatgtact 19260 ataacagtac tggtaacatg ggggtgctgg ctggtcaagc gtctcagtta aatgcagtgg 19320 ttgacttgca ggacagaaac acagaacttt cttaccaact cttgcttgac tctctgggcg 19380 acagaaccag atactttagc atgtggaatc aggctgtgga cagttatgat cctgatgtac 19440 gtgttattga aaatcatggt gtggaagatg aacttcccaa ctactgtttt ccactggacg 19500 gcataggtgt tccaacaacc agttacaaat caatagttcc aaatggagac aatgcgccta 19560 attggaagga acctgaagta aatggaacaa gtgagatcgg acagggtaat ttgtttgcca 19620 tggaaattaa ccttcaagcc aatctatggc gaagtttcct ttattccaat gtggctctat 19680 atctcccaga ctcgtacaaa tacaccccgt ccaatgtcac tcttccagaa aacaaaaaca 19740 cctacgacta catgaacggg cgggtggtgc cgccatctct agtagacacc tatgtgaaca 19800 ttggtgccag gtggtctctg gatgccatgg acaatgtcaa cccattcaac caccaccgta 19860 acgctggctt gcgttaccga tccatgcttc tgggtaacgg acgttatgtg cctttccaca 19920 tacaagtgcc tcaaaaattc ttcgctgtta aaaacctgct gcttctccca ggctcctaca 19980 cttatgagtg gaactttagg aaggatgtga acatggttct acagagttcc ctcggtaacg 20040 acctgcgggt agatggcgcc agcatcagtt tcacgagcat caacctctat gctacttttt 20100 tccccatggc tcacaacacc gcttccaccc ttgaagccat gctgcggaat gacaccaatg 20160 atcagtcatt caacgactac ctatctgcag ctaacatgct ctaccccatt cctgccaatg 20220 caaccaatat tcccatttcc attccttctc gcaactgggc ggctttcaga ggctggtcat 20280 ttaccagact gaaaaccaaa gaaactccct ctttggggtc tggatttgac ccctactttg 20340 tctattctgg ttctattccc tacctggatg gtaccttcta cctgaaccac acttttaaga 20400 aggtttccat catgtttgac tcttcagtga gctggcctgg aaatgacagg ttactatctc 20460 ctaacgaatt tgaaataaag cgcactgtgg atggcgaagg ctacaacgta gcccaatgca 20520 acatgaccaa agactggttc ttggtacaga tgctcgccaa ctacaacatc ggctatcagg 20580 gcttctacat tccagaagga tacaaagatc gcatgtattc atttttcaga aacttccagc 20640 ccatgagcag gcaggtggtt gatgaggtca attacaaaga cttcaaggcc gtcgccatac 20700 cctaccaaca caacaactct ggctttgtgg gttacatggc tccgaccatg cgccaaggtc 20760 aaccctatcc cgctaactat ccctatccac tcattggaac aactgccgta aatagtgtta 20820 cgcagaaaaa gttcttgtgt gacagaacca tgtggcgcat accgttctcg agcaacttca 20880 tgtctatggg ggcccttaca gacttgggac agaatatgct ctatgccaac tcagctcatg 20940 ctctggacat gacctttgag gtggatccca tggatgagcc caccctgctt tatcttctct 21000 tcgaagtttt cgacgtggtc agagtgcatc agccacaccg cggcatcatc gaggcagtct 21060 acctgcgtac accgttctcg gccggtaacg ctaccacgta agaagcttct tgcttcttgc 21120 aaatagcagc tgcaaccatg gcctgcggat cccaaaacgg ctccagcgag caagagctca 21180 gagccattgt ccaagacctg ggttgcggac cctatttttt gggaacctac gataagcgct 21240 tcccggggtt catggccccc gataagctcg cctgtgccat tgtaaatacg gccggacgtg 21300 agacgggggg agagcactgg ttggctttcg gttggaaccc acgttctaac acctgctacc 21360 tttttgatcc ttttggattc tcggatgatc gtctcaaaca gatttaccag tttgaatatg 21420 agggtctcct gcgccgcagc gctcttgcta ccaaggaccg ctgtattacg ctggaaaaat 21480 ctacccagac cgtgcagggt ccccgttctg ccgcctgcgg acttttctgc tgcatgttcc 21540 ttcacgcctt tgtgcactgg cctgaccgtc ccatggacgg aaaccccacc atgaaattgc 21600 taactggagt gccaaacaac atgcttcatt ctcctaaagt ccagcccacc ctgtgtgaca 21660 atcaaaaagc actctaccat tttcttaata cccattcgcc ttattttcgc tcccatcgta 21720 cacacatcga aagggccact gcgttcgacc gtatggatgt tcaataatga ctcatgtaaa 21780 caacgtgttc aataaacatc actttatttt tttacatgta tcaaggctct gcattactta 21840 tttatttaca agtcgaatgg gttctgacga gaatcagaat gacccgcagg cagtgatacg 21900 ttgcggaact gatacttggg ttgccacttg aattcgggaa tcaccaactt gggaaccggt 21960 atatcgggca ggatgtcact ccacagcttt ctggtcagct gcaaagctcc aagcaggtca 22020 ggagccgaaa tcttgaaatc acaattagga ccagtgcttt gagcgcgaga gttgcggtac 22080 accggattgc agcactgaaa caccatcagc gacggatgtc tcacgcttgc cagcacggtg 22140 ggatctgcaa tcatgcccac atccagatct tcagcattgg caatgctgaa cggggtcatc 22200 ttgcaggtct gcctacccat ggcgggcacc caattaggct tgtggttgca atcgcagtgc 22260 agggggatca gtatcatctt ggcctgatcc tgtctgattc ctggatacac ggctctcatg 22320 aaagcatcat attgcttgaa agcctgctgg gctttactac cctcggtata aaacatcccg 22380 caggacctgc tcgaaaactg gttagctgca cagccggcat cattcacaca gcagcgggcg 22440 tcattgttag ctatttgcac cacacttctg ccccagcggt tttgggtgat tttggttcgc 22500 tcgggattct cctttaaggc tcgttgtccg ttctcgctgg ccacatccat ctcgataatc 22560 tgctccttct gaatcataat attgccatgc aggcacttca gcttgccctc ataatcattg 22620 cagccatgag gccacaacgc acagcctgta cattcccaat tatggtgggc gatctgagaa 22680 aaagaatgta tcattccctg cagaaatctt cccatcatcg tgctcagtgt cttgtgacta 22740 gtgaaagtta actggatgcc tcggtgctcc tcgtttacgt actggtgaca gatgcgcttg 22800 tattgttcgt gttgctcagg cattagttta aaagaggttc taagttcgtt atccagcctg 22860 tacttctcca tcagcagaca catcacttcc atgcctttct cccaagcaga caccaggggc 22920 aagctaatcg gattcttaac agtgcaggca gcagctcctt tagccagagg gtcatcttta 22980 gcgatcttct caatgcttct tttgccatcc ttctcaacga tgcgcacggg cgggtagctg 23040 aaacccactg ctacaagttg cgcctcttct ctttcttctt cgctgtcttg actgatgtct 23100 tgcatgggga tatgtttggt cttccttggc ttctttttgg ggggtatcgg aggaggagga 23160 ctgtcgctcc gttccggaga cagggaggat tgtgacgttt cgctcaccat taccaactga 23220 ctgtcggtag aagaacctga ccccacacgg cgacaggtgt ttctcttcgg gggcagaggt 23280 ggaggcgatt gcgaagggct gcggtccgac ctggaaggcg gatgactggc agaacccctt 23340 ccgcgttcgg gggtgtgctc cctgtggcgg tcgcttaact gatttccttc gcggctggcc 23400 attgtgttct cctaggcaga gaaacaacag acatggaaac tcagccattg ctgtcaacat 23460 cgccacgagt gccatcacat ctcgtcctca gcgacgagga aaaggagcag agcttaagca 23520 ttccaccgcc cagtcctgcc accacctcta ccctagaaga taaggaggtc gacgcatctc 23580 atgacatgca gaataaaaaa gcgaaagagt ctgagacaga catcgagcaa gacccgggct 23640 atgtgacacc ggtggaacac gaggaagagt tgaaacgctt tctagagaga gaggatgaaa 23700 actgcccaaa acaacgagca gataactatc accaagatgc tggaaatagg gatcagaaca 23760 ccgactacct catagggctt gacggggaag acgcgctcct taaacatcta gcaagacagt 23820 cgctcatagt caaggatgca ttattggaca gaactgaagt gcccatcagt gtggaagagc 23880 tcagccgcgc ctacgagctt aacctctttt cacctcgtac tccccccaaa cgtcagccaa 23940 acggcacctg cgagccaaat cctcgcttaa acttttatcc agcttttgct gtgccagaag 24000 tactggctac ctatcacatc ttttttaaaa atcaaaaaat tccagtctcc tgccgcgcta 24060 atcgcacccg cgccgatgcc ctactcaatc tgggacctgg ttcacgctta cctgatatag 24120 cttccttgga agaggttcca aagatcttcg agggtctggg caataatgag actcgggccg 24180 caaatgctct gcaaaaggga gaaaatggca tggatgagca tcacagcgtt ctggtggaat 24 240 tggaaggcga taatgccaga ctcgcagtac tcaagcgaag catcgaggtc acacacttcg 24300 catatcccgc tgtcaacctg ccccctaaag tcatgacggc ggtcatggac cagttactca 24360 ttaagcgcgc aagtcccctt tcagaagaca tgcatgaccc agatgcctgt gatgagggta 24420 aaccagtggt cagtgatgag cagctaaccc gatggctggg caccgactct cccagggatt 24480 tggaagagcg tcgcaagctt atgatggccg tggtgctggt taccgtagaa ctagagtgtc 24540 tccgacgttt ctttaccgat tcagaaacct tgcgcaaact cgaagagaat ctgcactaca 24600 cttttagaca cggctttgtg cggcaggcat gcaagatatc taacgtggaa ctcaccaacc 24660 tggtttccta catgggtatt ctgcatgaga atcgcctagg acaaagcgtg ctgcacagca 24720 ccctgaaggg ggaagcccgc cgtgattaca tccgcgattg tgtctatctg tacctgtgcc 24780 acacgtggca aaccggcatg ggtgtatggc agcaatgttt agaagaacag aacttgaaag 24840 agcttgacaa gctcttacag aaatctctta aggttctgtg gacagggttc gacgagcgca 24900 ccgtcgcttc cgacctggca gacctcatct tcccagagcg tctcagggtt actttgcgaa 24960 acggattgcc tgactttatg agccagagca tgcttaacaa ttttcgctct ttcatcctgg 25020 aacgctccgg tatcctgccc gccacctgct gcgcactgcc ctccgacttt gtgcctctca 25080 cctaccgcga gtgccccccg ccgctatgga gtcactgcta cctgttccgt ctggccaact 25 140 atctctccta ccactcggat gtgatcgagg atgtgagcgg agacggcttg ctggagtgtc 25200 actgccgctg caatctgtgc acgccccacc ggtccctagc ttgcaacccc cagttgatga 25260 gcgaaaccca gataataggc acctttgaat tgcaaggccc cagcagccaa ggcgatgggt 25320 cttctcctgg gcaaagttta aaactgaccc cgggactgtg gacctccgcc tacttgcgca 25380 agtttgctcc ggaagattac cacccctatg aaatcaagtt ctatgaggac caatcacagc 25440 ctccaaaggc cgaactttcg gcctgcgtca tcacccaggg ggcaattctg gcccaattgc 25500 aagccatcca aaaatcccgc caagaatttc tactgaaaaa gggtaagggg gtctaccttg 25560 acccccagac cggcgaggaa ctcaacacaa ggttccctca ggatgtccca acgacgagaa 25620 aacaagaagt tgaaggtgca gccgccgccc ccagaagata tggaggaaga ttgggacagt 25680 caggcagagg aggcggagga ggacagtctg gaggacagtc tggaggaaga cagtttggag 25740 gaggaaaacg aggaggcaga ggaggtggaa gaagtaaccg ccgacaaaca gttatcctcg 25800 gctgcggaga caagcaacag cgctaccatc tccgctccga gtcgaggaac ccggcggcgt 25860 cccagcagta gatgggacga gaccggacgc ttcccgaacc caaccagcgc ttccaagacc 25920 ggtaagaagg atcggcaggg atacaagtcc tggcgggggc ataagaatgc catcatctcc 25980 tgcttgcatg agtgcggggg caacatatcc ttcacgcggc gctacttgct attccaccat 26040 ggggtgaact ttccgcgcaa tgttttgcat tactaccgtc acctccacag cccctactat 26100 agccagcaaa tcccggcagt ctcgacagat aaagacagcg gcggcgacct ccaacagaaa 26160 accagcagcg gcagttagaa aatacacaac aagtgcagca acaggaggat taaagattac 26220 agccaacgag ccagcgcaaa cccgagagtt aagaaatcgg atctttccaa ccctgtatgc 26280 catcttccag cagagtcggg gtcaagagca ggaactgaaa ataaaaaacc gatctctgcg 26340 ttcgctcacc agaagttgtt tgtatcacaa gagcgaagat caacttcagc gcactctcga 26400 ggacgccgag gctctcttca acaagtactg cgcgctgact cttaaagagt aggcagcgac 26460 cgcgcttatt caaaaaaggc gggaattaca tcatcctcga catgagtaaa gaaattccca 26520 cgccttacat gtggagttat caaccccaaa tgggattggc ggcaggcgcc tcccaggact 26580 actccacccg catgaattgg ctcagcgccg ggccttctat gatttctcga gttaatgata 26640 tacgcgccta ccgaaaccaa atacttttgg aacagtcagc tcttaccacc acgccccgcc 26700 aacaccttaa tcccagaaat tggcccgccg ccctagtgta ccaggaaagt cccgctccca 26760 ccactgtatt acttcctcga gacgcccagg ccgaagtcca aatgactaat gcaggtgcgc 26820 agttagctgg cggctccacc ctatgtcgtc acaggcctcg gcataatata aaacgcctga 26880 tgatcagagg ccgaggtatc cagctcaacg acgagtcggt gagctctccg cttggtctac 26940 gaccagacgg aatctttcag attgccggct gcgggagatc ttccttcacc cctcgtcagg 27000 ctgttctgac tttggaaagt tcgtcttcgc aaccccgctc gggcggaatc gggaccgttc 27060 aatttgtgga ggagtttact ccctctgtct acttcaaccc cttctccgga tctcctgggc 27120 attacccgga cgagttcata ccgaacttcg acgcgattag cgagtcagtg gacggctacg 27180 attgatgtct ggtgacgcgg ctgagctatc tcggctgcga catctagacc actgccgccg 27240 ctttcgctgc tttgcccggg aactcattga gttcatctac ttcgaactcc ccaaggatca 27300 ccctcaaggt ccggcccacg gagtgcggat ttctatcgaa ggcaaaatag actctcgcct 27360 gcaacgaatt ttctcccagc ggcccgtgct gatcgagcga gaccagggaa acaccacggt 27420 ttccatctac tgcatttgta atcaccccgg attgcatgaa agcctttgct gtcttatgtg 27480 tactgagttt aataaaaact gaattaagac tctcctacgg actgccgctt cttcaacccg 27540 gattttacaa ccagaagaac gaaacttttc ctgtcgtcca ggactctgtt aacttcacct 27600 ttcctactca caaactagaa gctcaacgac tacaccgctt ttccagaagc attttcccta 27660 ctaatactac tttcaaaacc ggaggtgagc tccaaggtct tcctacagaa aacccttggg 27720 tggaagcggg ccttgtagtg ctaggaattc ttgcgggtgg gcttgtgatt attctttgct 27780 acctatacac accttgcttc actttcttag tggtgttgtg gtattggttt aaaaaatggg 27840 gcccatacta gtcttgcttg ttttactttc gcttttggaa ccgggttctg ccaattacga 27900 tccatgtcta gacttcgacc cagaaaactg cacacttact tttgcacccg acacaagccg 27960 catctgtgga gttcatcgcc tctcttacga acttggcccc caacgacaaa aatttacctg 28020 catggtggga atcaacccca tagttatcac ccagcaaagt ggagatacta agggttgcat 28080 tcactgctcc tgcgattcca tcgagtgcac ctacaccctg ctgaagaccc tatgcggcct 28140 aagagacctg ctaccaatga attaaaaaat gattaataaa aaatcactta cttgaaatca 28200 gcaataaggt ctctgttgaa attttctccc agcagcacct cacttccctc ttcccaactc 28260 tggtattcta aaccccgttc agcggcatac tttctccata ctttaaaggg gatgtcaaat 28320 tttagctcct ctcctgtacc cacaatcttc atgtctttct tcccagatga ccaagagagt 28380 ccggctcagt gactccttca accctgtcta cccctatgaa gatgaaagca cctcccaaca 28440 cccctttata aacccagggt ttatttcccc aaatggcttc acacaaagcc caaacggagt 28500 tcttacttta aaatgtttaa ccccactaac aaccacaggc ggatctctac agctaaaagt 28560 gggaggggga cttacagtgg atgacaccaa cggttttttg aaagaaaaca taagtgccac 28620 cacaccactc gttaagactg gtcactctat aggtttacca ctaggagccg gattgggaac 28680 gaatgaaaat aaactttgta tcaaattagg acaaggactt acattcaatt caaacaacat 28740 ttgcattgat gacaatatta acaccttatg gacaggagtc aaccccaccg aagccaactg 28800 tcaaatcatg aactccagtg aatctaatga ttgcaaatta attctaacac tagttaaaac 28860 tggagcacta gtcactgcat ttgtttatgt tataggagta tctaacaatt ttaatatgct 28920 aactacacac agaaatataa attttactgc agagctgttt ttcgattcta ctggtaattt 28980 actaactaga ctctcatccc tcaaaactcc acttaatcat aaatcaggac aaaacatggc 29040 tactggtgcc attactaatg ctaaaggttt catgcccagc acgactgcct atcctttcaa 29100 tgataattct agagaaaaag aaaactacat ttacggaact tgttactaca cagctagtga 29160 tcgcactgct tttcccattg acatatctgt catgcttaac cgaagagcaa taaatgacga 29220 gacatcatat tgtattcgta taacttggtc ctggaacaca ggagatgccc cagaggtgca 29280 aacctctgct acaaccctag tcacctcccc atttaccttt tactacatca gagaagacga 29340 ctgacaaata aagtttgcga tcgccaggcc caccatgggc cacacacgga ggcagggaac 29400 atcaccatcc aagtgtccat acctcaattt ctttcagctc ttggtgctgg ctggtctttc 29460 tcacttctgt tcaggtgtta tccacgtgac caaggaagtg aaagaagtgg caacgctgtc 29520 ctgtggtcac aatgtttctg ttgaagagct ggcacaaact cgcatctact ggcaaaagga 29580 gaagaaaatg gtgctgacta tgatgtctgg ggacatgaat atatggcccg agtacaagaa 29640 ccggaccatc tttgatatca ctaataacct ctccattgtg atcctggctc tgcgcccatc 29700 tgacgagggc acatacgagt gtgttgttct gaagtatgaa aaagacgctt tcaagcggga 29760 acacctggct gaagtgacgt tatcagtcaa agctgacttc cctacaccta gtatatctga 29820 ctttgaaatt ccaacttcta atattagaag gataatttgc tcaacctctg gaggttttcc 29880 agagcctcac ctctcctggt tggaaaatgg agaagaatta aatgccatca acacaacagt 29940 ttcccaagat cctgaaactg agctctatgc tgttagcagc aaactggatt tcaatatgac 30000 aaccaaccac agcttcatgt gtctcatcaa gtatggacat ttaagagtga atcagacctt 30060 caactggaat acaaccaagc aagagcattt tcctgataac ctgctcccat cctgggccat 30120 taccttaatc tcagtaaatg gaatttttgt gatatgctgc ctgacctact gctttgcccc 30180 aagatgcaga gagagaagga ggaatgagag attgagaagg gaaagtgtac gccctgtata 30240 agctagcttg actgactgag atacagcgta ccttcagctc acagacatga taagatacat 30300 tgatgagttt ggacaaacca caactagaat gcagtgaaaa aaatgcttta tttgtgaaat 30360 ttgtgatgct attgctttat ttgtaaccat tataagctgc aataaacaag ttaacaacaa 30420 caattgcatt cattttatgt ttcaggttca gggggaggtg tgggaggttt tttaaagcaa 30480 gtaaaacctc tacaaatgtg gtagtcgtca gctatcctgc aggaacttgt ttatttgaaa 30540 atcaattcac aaaatccgag tagttatttt gcctccccct tcccatttaa cagaatacac 30600 caatctctcc ccacgcacag ctttaaacat ttggatacca ttagatatag acatggtttt 30660 agattccaca ttccaaacag tttcagagcg agccaatctg gggtcagtga tagataaaaa 30720 tccatcggga tagtctttta aagcgctttc acagtccaac tgctgcggat gcgactccgg 30780 agtctggatc acggtcatct ggaagaagaa cgatgggaat cataatccga aaacggtatc 30840 ggacgattgt gtctcatcaa acccacaagc agccgctgtc tgcgtcgctc cgtgcgactg 30900 ctgtttatgg gatcagggtc cacagtgtcc tgaagcatga ttttaatagc ccttaacatc 30960 aactttctgg tgcgatgcgc gcagcaacgc attctgattt cactcaaatc tttgcagtag 31020 gtacaacaca ttattacaat attgtttaat aaaccataat taaaagcgct ccagccaaaa 31080 ctcatatctg atataatcgc ccctgcatga ccatcatacc aaagtttaat ataaattaaa 31140 tgacgttccc tcaaaaacac actacccaca tacatgatct cttttggcat gtgcatatta 31200 acaatctgtc tgtaccatgg acaacgttgg ttaatcatgc aacccaatat aaccttccgg 31260 aaccacactg ccaacaccgc tcccccagcc atgcattgaa gtgaaccctg ctgattacaa 31320 tgacaatgaa gaacccaatt ctctcgaccg tgaatcactt gagaatgaaa aatatctata 31380 gtggcacaac atagacataa atgcatgcat cttctcataa tttttaactc ctcaggattt 31440 agaaacatat cccagggaat aggaagctct tgcagaacag taaagctggc agaacaagga 31500 agaccacgaa cacaacttac actatgcata gtcatagtat cacaatctgg caacagcggg 31560 tggtcttcag tcatagaagc tcgggtttca ttttcctcac aacgtggtaa ctgggctctg 31620 gtgtaagggt gatgtctggc gcatgatgtc gagcgtgcgc gcaaccttgt cataatggag 31680 ttgcttcctg acattctcgt attttgtata gcaaaacgcg gccctggcag aacacactct 31740 tcttcgcctt ctatcctgcc gcttagcgtg ttccgtgtga tagttcaagt acaaccacac 31800 tcttaagttg gtcaaaagaa tgctggcttc agttgtaatc aaaactccat cgcatctaat 31860 cgttctgagg aaatcatcca agcaatgcaa ctggattgtg tttcaagcag gagaggagag 31920 ggaagagacg gaagaaccat gttaattttt attccaaacg atctcgcagt acttcaaatt 31980 gtagatcgcg cagatggcat ctctcgcccc cactgtgttg gtgaaaaagc acagctagat 32040 caaaagaaat gcgattttca aggtgctcaa cggtggcttc cagcaaagcc tccacgcgca 32 100 catccaagaa caaaagaata ccaaaagaag gagcattttc taactcctca atcatcatat 32160 tacattcctg caccattccc agataatttt cagctttcca gccttgaatt attcgtgtca 32220 gttcttgtgg taaatccaat ccacacatta caaacaggtc ccggagggcg ccctccacca 32280 ccattcttaa acacaccctc ataatgacaa aatatcttgc tcctgtgtca cctgtagcga 32340 attgagaatg gcaacatcaa ttgacatgcc cttggctcta agttcttctt taagttctag 32400 ttgtaaaaac tctctcatat tatcaccaaa ctgcttagcc agaagccccc cgggaacaag 32460 agcaggggac gctacagtgc agtacaagcg cagacctccc caattggctc cagcaaaaac 32520 aagattggaa taagcatatt gggaaccgcc agtaatatca tcgaagttgc tggaaatata 32580 atcaggcaga gtttcttgta aaaattgaat aaaagaaaaa tttgccaaaa aaacattcaa 32640 aacctctggg atgcaaatgc aataggttac cgcgctgcgc tccaacattg ttagttttga 32700 attagtctgc aaaaataaaa aaaaaaacaa gcgtcatatc atagtagcct gacgaacaga 32760 tggataaatc agtctttcca tcacaagaca agccacaggg tctccagctc gaccctcgta 32820 aaacctgtca tcatgattaa acaacagcac cgaaagttcc tcgcggtgac cagcatgaat 32880 aattcttgat gaagcataca atccagacat gttagcatca gttaacgaga aaaaacagcc 32940 aacatagcct ttgggtataa ttatgcttaa tcgtaagtat agcaaagcca cccctcgcgg 33000 atacaaagta aaaggcacag gagaataaaa aatataatta tttctctgct gctgttcagg 33060 caacgtcgcc cccggtccct ctaaatacac atacaaagcc tcatcagcca tggcttacca 33 120 gacaaagtac agcgggcaca caaagcacaa gctctaaagt gactctccaa cctctccaca 33180 atatatatat acacaagccc taaactgacg taatgggagt aaagtgtaaa aaatcccgcc 33240 aaacccaaca cacaccccga aactgcgtca ccagggaaaa gtacagtttc acttccgcaa 33300 tcccaacagg cgtaacttcc tctttctcac ggtacgtgat atcccactaa cttgcaacgt 33360 cattttccca cggtcgcacc gcccctttta gccgttaacc ccacagccaa tcaccacacg 33420 atccacactt tttaaaatca cctcatttac atattggcac cattccatct ataaggtata 33480 ttatatagat aga 33493 <210> 17 <211> 34119 <212> DNA <213> Artificial Sequence <220> <223> NG-343 virus genome sequence comprising the EnAd genome with a transgene cassette that encodes IFNa, and CD80, inserted in the region By. The transgene cassette contains a 5'SSA, IFNa cDNA sequence, P2A peptide, CD80 cDNA sequence and a 3'poly(A) <400> 17 tctatctata taatatacct tatagatgga atggtgccaa tatgtaaatg aggtgatttt 60 aaaaagtgtg gatcgtgtgg tgattggctg tggggttaac ggctaaaagg ggcggtgcga 120 ccgtgggaaa atgacgtttt gtgggggtgg agtttttttg caagttgtcg cgggaaatgt 180 gacgcataaa aaggcttttt tctcacggaa ctacttagtt ttcccacggt atttaacagg 240 aaatgaggta gttttgaccg gatgcaagtg aaaattgttg attttcgcgc gaaaactgaa 300 tgaggaagtg tttttctgaa taatgtggta tttatggcag ggtggagtat ttgttcaggg 360 ccaggtagac tttgacccat tacgtggagg tttcgattac cgtgtttttt acctgaattt 420 ccgcgtaccg tgtcaaagtc ttctgttttt acgtaggtgt cagctgatcg ctagggtatt 480 tatacctcag ggtttgtgtc aagaggccac tcttgagtgc cagcgagaag agttttctcc 540 tctgcgccgg cagtttaata ataaaaaaat gagagatttg cgatttctgc ctcaggaaat 600 aatctctgct gagactggaa atgaaatatt ggagcttgtg gtgcacgccc tgatgggaga 660 cgatccggag ccacctgtgc agctttttga gcctcctacg cttcaggaac tgtatgattt 720 agaggtagag ggatcggagg attctaatga ggaagctgta aatggctttt ttaccgattc 780 tatgctttta gctgctaatg aagggttaga attagatccg cctttggaca cttttgatac 840 tccaggggta attgtggaaa gcggtacagg tgtaagaaaa ttacctgatt tgagttccgt 900 ggactgtgat ttgcactgct atgaagacgg gtttcctccg agtgatgagg aggaccatga 960 aaaggagcag tccatgcaga ctgcagcggg tgagggagtg aaggctgcca atgttggttt 1020 tcagttggat tgcccggagc ttcctggaca tggctgtaag tcttgtgaat ttcacaggaa 1080 aaatactgga gtaaaggaac tgttatgttc gctttgttat atgagaacgc actgccactt 1140 tatttacagt aagtgtgttt aagttaaaat ttaaaggaat atgctgtttt tcacatgtat 1200 attgagtgtg agttttgtgc ttcttattat aggtcctgtg tctgatgctg atgaatcacc 1260 atctcctgat tctactacct cacctcctga gattcaagca cctgttcctg tggacgtgcg 1320 caagcccatt cctgtgaagc ttaagcctgg gaaacgtcca gcagtggaaa aacttgagga 1380 cttgttacag ggtggggacg gacctttgga cttgagtaca cggaaacgtc caagacaata 1440 agtgttccat atccgtgttt acttaaggtg acgtcaatat ttgtgtgaca gtgcaatgta 1500 ataaaaatat gttaactgtt cactggtttt tattgctttt tgggcgggga ctcaggtata 1560 taagtagaag cagacctgtg tggttagctc ataggagctg gctttcatcc atggaggttt 1620 gggccatttt ggaagacctt aggaagacta ggcaactgtt agagaacgct tcggacggag 1680 tctccggttt ttggagattc tggttcgcta gtgaattagc tagggtagtt tttaggataa 1740 aacaggacta taaacaagaa tttgaaaagt tgttggtaga ttgcccagga ctttttgaag 1800 ctcttaattt gggccatcag gttcacttta aagaaaaagt tttatcagtt ttagactttt 1860 caaccccagg tagaactgct gctgctgtgg cttttcttac ttttatatta gataaatgga 1920 tcccgcagac tcatttcagc aggggatacg ttttggattt catagccaca gcattgtgga 1980 gaacatggaa ggttcgcaag atgaggacaa tcttaggtta ctggccagtg cagcctttgg 2040 gtgtagcggg aatcctgagg catccaccgg tcatgccagc ggttctggag gaggaacagc 2100 aagaggacaa cccgagagcc ggcctggacc ctccagtgga ggaggcggag tagctgactt 2160 gtctcctgaa ctgcaacggg tgcttactgg atctacgtcc actggacggg ataggggcgt 2220 taagagggag agggcatcta gtggtactga tgctagatct gagttggctt taagtttaat 2280 gagtcgcaga cgtcctgaaa ccatttggtg gcatgaggtt cagaaagagg gaagggatga 2340 agtttctgta ttgcaggaga aatattcact ggaacaggtg aaaacatgtt ggttggagcc 2400 tgaggatgat tgggaggtgg ccattaaaaa ttatgccaag atagctttga ggcctgataa 2460 acagtataag attactagac ggattaatat ccggaatgct tgttacatat ctggaaatgg 2520 ggctgaggtg gtaatagata ctcaagacaa ggcagttatt agatgctgca tgatggatat 2580 gtggcctggg gtagtcggta tggaagcagt aacttttgta aatgttaagt ttaggggaga 2640 tggttataat ggaatagtgt ttatggccaa taccaaactt atattgcatg gttgtagctt 2700 ttttggtttc aacaatacct gtgtagatgc ctggggacag gttagtgtac ggggatgtag 2760 tttctatgcg tgttggattg ccacagctgg cagaaccaag agtcaattgt ctctgaagaa 2820 atgcatattt caaagatgta acctgggcat tctgaatgaa ggcgaagcaa gggtccgcca 2880 ctgcgcttct acagatactg gatgttttat tttgattaag ggaaatgcca gcgtaaagca 2940 taacatgatt tgcggtgctt ccgatgagag gccttatcaa atgctcactt gtgctggtgg 3000 gcattgtaat atgctggcta ctgtgcatat tgtttcccat caacgcaaaa aatggcctgt 3060 ttttgatcac aatgtgatga cgaagtgtac catgcatgca ggtgggcgta gaggaatgtt 3120 tatgccttac cagtgtaaca tgaatcatgt gaaagtgttg ttggaaccag atgccttttc 3180 cagaatgagc ctaacaggaa tttttgacat gaacatgcaa atctggaaga tcctgaggta 3240 tgatgatacg agatcgaggg tacgcgcatg cgaatgcgga ggcaagcatg ccaggttcca 3300 gccggtgtgt gtagatgtga ctgaagatct cagaccggat catttggtta ttgcccgcac 3360 tggagcagag ttcggatcca gtggagaaga aactgactaa ggtgagtatt gggaaaactt 3420 tggggtggga ttttcagatg gacagattga gtaaaaattt gttttttctg tcttgcagct 3480 gtcatgagtg gaaacgcttc ttttaagggg ggagtcttca gcccttatct gacagggcgt 3540 ctcccatcct gggcaggagt tcgtcagaat gttatgggat ctactgtgga tggaagaccc 3600 gtccaacccg ccaattcttc aacgctgacc tatgctactt taagttcttc acctttggac 3660 gcagctgcag ctgccgccgc cgcttctgtt gccgctaaca ctgtgcttgg aatgggttac 3720 tatggaagca tcatggctaa ttccacttcc tctaataacc cttctaccct gactcaggac 3780 aagttacttg tccttttggc ccagctggag gctttgaccc aacgtctggg tgaactttct 3840 cagcaggtgg tcgagttgcg agtacaaact gagtctgctg tcggcacggc aaagtctaaa 3900 taaaaaaatc ccagaatcaa tgaataaata aacaagcttg ttgttgattt aaaatcaagt 3960 gtttttattt catttttcgc gcacggtatg ccctagacca ccgatctcta tcattgagaa 4020 ctcggtggat tttttccagg atcctataga ggtgggattg aatgtttaga tacatgggca 4080 ttaggccgtc tttggggtgg agatagctcc attgaaggga ttcatgctcc ggggtagtgt 4140 tgtaaatcac ccagtcataa caaggtcgca gtgcatggtg ttgcacaata tcttttagaa 4200 gtaggctgat tgccacagat aagcccttgg tgtaggtgtt tacaaaccgg ttgagctggg 4260 atgggtgcat tcggggtgaa attatgtgca ttttggattg gatttttaag ttggcaatat 4320 tgccgccaag atcccgtctt gggttcatgt tatgaaggac caccaagacg gtgtatccgg 4380 tacatttagg aaatttatcg tgcagcttgg atggaaaagc gtggaaaaat ttggagacac 4440 ccttgtgtcc tccaagattt tccatgcact catccatgat aatagcaatg gggccgtggg 4500 cagcggcgcg ggcaaacacg ttccgtgggt ctgacacatc atagttatgt tcctgagtta 4560 aatcatcata agccatttta atgaatttgg ggcggagagt accagattgg ggtatgaatg 4620 ttccttcggg ccccggagca tagttcccct cacagatttg catttcccaa gctttcagtt 4680 ccgagggtgg aatcatgtcc acctgggggg ctatgaaaaa caccgtttct ggggcggggg 4740 tgattaattg tgatgatagc aaatttctga gcaattgaga tttgccacat ccggtggggc 4800 cataaatgat tccgattacg ggttgcaggt ggtagtttag ggaacggcaa ctgccgtctt 4860 ctcgaagcaa gggggccacc tcgttcatca tttcccttac atgcatattt tcccgcacca 4920 aatccattag gaggcgctct cctcctagtg atagaagttc ttgtagtgag gaaaagtttt 4980 tcagcggttt cagaccgtca gccatgggca ttttggagag agtttgctgc aaaagttcta 5040 gtctgttcca cagttcagtg atgtgttcta tggcatctcg atccagcaga cctcctcgtt 5100 tcgcgggttt ggacggctcc tggaataggg tatgagacga tgggcgtcca gcgctgccag 5160 ggttcggtcc ttccagggtc tcagtgttcg agtcagggtt gtttccgtca cagtgaaggg 5220 gtgtgcgcct gcttgggcgc ttgccagggt gcgcttcaga ctcatcctgc tggtcgaaaa 5280 cttctgtcgc ttggcgccct gtatgtcggc caagtagcag tttaccatga gttcgtagtt 5340 gagcgcctcg gctgcgtggc ctttggcgcg gagcttacct ttggaagttt tcttgcatac 5400 cgggcagtat aggcatttca gcgcatacaa cttgggcgca aggaaaacgg attctgggga 5460 gtatgcatct gcgccgcagg aggcgcaaac agtttcacat tccaccagcc aggttaaatc 5520 cggttcattg gggtcaaaaa caagttttcc gccatatttt ttgatgcgtt tcttaccttt 5580 ggtctccatg agttcgtgtc ctcgttgagt gacaaacagg ctgtccgtgt ccccgtagac 5640 tgattttaca ggcctcttct ccagtggagt gcctcggtct tcttcgtaca ggaactctga 5700 ccactctgat acaaaggcgc gcgtccaggc cagcacaaag gaggctatgt gggaggggta 5760 gcgatcgttg tcaaccaggg ggtccacctt ttccaaagta tgcaaacaca tgtcaccctc 5820 ttcaacatcc aggaatgtga ttggcttgta ggtgtatttc acgtgacctg gggtccccgc 5880 tgggggggta taaaaggggg cggttctttg ctcttcctca ctgtcttccg gatcgctgtc 5940 caggaacgtc agctgttggg gtaggtattc cctctcgaag gcgggcatga cctctgcact 6000 caggttgtca gtttctaaga acgaggagga tttgatattg acagtgccgg ttgagatgcc 6060 tttcatgagg ttttcgtcca tctggtcaga aaacacaatt tttttattgt caagtttggt 6120 ggcaaatgat ccatacaggg cgttggataa aagtttggca atggatcgca tggtttggtt 6180 cttttccttg tccgcgcgct ctttggcggc gatgttgagt tggacatact cgcgtgccag 6240 gcacttccat tcggggaaga tagttgttaa ttcatctggc acgattctca cttgccaccc 6300 tcgattatgc aaggtaatta aatccacact ggtggccacc tcgcctcgaa ggggttcatt 6360 ggtccaacag agcctacctc ctttcctaga acagaaaggg ggaagtgggt ctagcataag 6420 ttcatcggga gggtctgcat ccatggtaaa gattcccgga agtaaatcct tatcaaaata 6480 gctgatggga gtggggtcat ctaaggccat ttgccattct cgagctgcca gtgcgcgctc 6540 atatgggtta aggggactgc cccatggcat gggatgggtg agtgcagagg catacatgcc 6600 acagatgtca tagacgtaga tgggatcctc aaagatgcct atgtaggttg gatagcatcg 6660 cccccctctg atacttgctc gcacatagtc atatagttca tgtgatggcg ctagcagccc 6720 cggacccaag ttggtgcgat tgggtttttc tgttctgtag acgatctggc gaaagatggc 6780 gtgagaattg gaagagatgg tgggtctttg aaaaatgttg aaatgggcat gaggtagacc 6840 tacagagtct ctgacaaagt gggcataaga ttcttgaagc ttggttacca gttcggcggt 6900 gacaagtacg tctagggcgc agtagtcaag tgtttcttga atgatgtcat aacctggttg 6960 gtttttcttt tcccacagtt cgcggttgag aaggtattct tcgcgatcct tccagtactc 7020 ttctagcgga aacccgtctt tgtctgcacg gtaagatcct agcatgtaga actgattaac 7080 tgccttgtaa gggcagcagc ccttctctac gggtagagag tatgcttgag cagcttttcg 7140 tagcgaagcg tgagtaaggg caaaggtgtc tctgaccatg actttgagga attggtattt 7200 gaagtcgatg tcgtcacagg ctccctgttc ccagagttgg aagtctaccc gtttcttgta 7260 ggcggggttg ggcaaagcga aagtaacatc attgaagaga atcttgccgg ccctgggcat 7320 gaaattgcga gtgatgcgaa aaggctgtgg tacttccgct cggttattga taacctgggc 7380 agctaggacg atctcgtcga aaccgttgat gttgtgtcct acgatgtata attctatgaa 7440 acgcggcgtg cctctgacgt gaggtagctt actgagctca tcaaaggtta ggtctgtggg 7500 gtcagataag gcgtagtgtt cgagagccca ttcgtgcagg tgaggattcg ctttaaggaa 7560 ggaggaccag aggtccactg ccagtgctgt ttgtaactgg tcccggtact gacgaaaatg 7620 ccgtccgact gccatttttt ctggggtgac gcaatagaag gtttgggggt cctgccgcca 7680 gcgatcccac ttgagtttta tggcgaggtc ataggcgatg ttgacgagcc gctggtctcc 7740 agagagtttc atgaccagca tgaaggggat tagctgcttg ccaaaggacc ccatccaggt 7800 gtaggtttcc acatcgtagg tgagaaagag cctttctgtg cgaggatgag agccaatcgg 7860 gaagaactgg atctcctgcc accagttgga ggaatggctg ttgatgtgat ggaagtagaa 7920 ctccctgcga cgcgccgagc attcatgctt gtgcttgtac agacggccgc agtagtcgca 7980 gcgttgcacg ggttgtatct cgtgaatgag ttgtacctgg cttcccttga cgagaaattt 8040 cagtgggaag ccgaggcctg gcgattgtat ctcgtgcttt actatgttgt ctgcatcggc 8100 ctgttcatct tctgtctcga tggtggtcat gctgacgagc cctcgcggga ggcaagtcca 8160 gacctcggcg cggcaggggc ggagctcgag gacgagagcg cgcaggctgg agctgtccag 8220 ggtcctgaga cgctgcggac tcaggttagt aggcagtgtc aggagattaa cttgcatgat 8280 cttttggagg gcgtgcggga ggttcagata gtacttgatc tcaacgggtc cgttggtgga 8340 gatgtcgatg gcttgcaggg ttccgtgtcc cttgggcgct accaccgtgc ccttgttttt 8400 cattttggac ggcggtggct ctgttgcttc ttgcatgttt agaagcggtg tcgagggcgc 8460 gcaccgggcg gcaggggcgg ctcgggaccc ggcggcatgg ctggcagtgg tacgtcggcg 8520 ccgcgcgcgg gtaggttctg gtactgcgcc ctgagaagac tcgcatgcgc gacgacgcgg 8580 cggttgacat cctggatctg acgcctctgg gtgaaagcta ccggccccgt gagcttgaac 8640 ctgaaagaga gttcaacaga atcaatctcg gtatcgttga cggcggcttg cctaaggatt 8700 tcttgcacgt caccagagtt gtcctggtag gcgatctccg ccatgaactg ctcgatctct 8760 tcctcttgaa gatctccgcg gcccgctctc tcgacggtgg ccgcgaggtc gttggagatg 8820 cgcccaatga gttgagagaa tgcattcatg cccgcctcgt tccagacgcg gctgtagacc 8880 acggccccca cgggatctct cgcgcgcatg accacctggg cgaggttgag ctccacgtgg 8940 cgggtgaaga ccgcatagtt gcataggcgc tggaaaaggt agttgagtgt ggtggcgatg 9000 tgctcggtga cgaagaaata catgatccat cgtctcagcg gcatctcgct gacatcgccc 9060 agagcttcca agcgctccat ggcctcgtag aagtccacgg caaaattaaa aaactgggag 9120 tttcgcgcgg acacggtcaa ctcctcttcc agaagacgga taagttcggc gatggtggtg 9180 cgcacctcgc gctcgaaagc ccctgggatt tcttcctcaa tctcttcttc ttccactaac 9240 atctcttcct cttcaggtgg ggctgcagga ggagggggaa cgcggcgacg ccggcggcgc 9300 acgggcagac ggtcgatgaa tctttcaatg acctctccgc ggcggcggcg catggtttca 9360 gtgacggcgc ggccgttctc gcgcggtcgc agagtaaaaa caccgccgcg catctcctta 9420 aagtggtgac tgggaggttc tccgtttggg agggagaggg cgctgattat acattttatt 9480 aattggcccg tagggactgc acgcagagat ctgatcgtgt caagatccac gggatctgaa 9540 aacctttcga cgaaagcgtc taaccagtca cagtcacaag gtaggctgag tacggcttct 9600 tgtgggcggg ggtggttatg tgttcggtct gggtcttctg tttcttcttc atctcgggaa 9660 ggtgagacga tgctgctggt gatgaaatta aagtaggcag ttctaagacg gcggatggtg 9720 gcgaggagca ccaggtcttt gggtccggct tgctggatac gcaggcgatt ggccattccc 9780 caagcattat cctgacatct agcaagatct ttgtagtagt cttgcatgag ccgttctacg 9840 ggcacttctt cctcacccgt tctgccatgc atacgtgtga gtccaaatcc gcgcattggt 9900 tgtaccagtg ccaagtcagc tacgactctt tcggcgagga tggcttgctg tacttgggta 9960 agggtggctt gaaagtcatc aaaatccaca aagcggtggt aagctcctgt attaatggtg 10020 taagcacagt tggccatgac tgaccagtta actgtctggt gaccagggcg cacgagctcg 10080 gtgtatttaa ggcgcgaata ggcgcgggtg tcaaagatgt aatcgttgca ggtgcgcacc 10140 agatactggt accctataag aaaatgcggc ggtggttggc ggtagagagg ccatcgttct 10200 gtagctggag cgccaggggc gaggtcttcc aacataaggc ggtgatagcc gtagatgtac 10260 ctggacatcc aggtgattcc tgcggcggta gtagaagccc gaggaaactc gcgtacgcgg 10320 ttccaaatgt tgcgtagcgg catgaagtag ttcattgtag gcacggtttg accagtgagg 10380 cgcgcgcagt cattgatgct ctatagacac ggagaaaatg aaagcgttca gcgactcgac 10440 tccgtagcct ggaggaacgt gaacgggttg ggtcgcggtg taccccggtt cgagacttgt 10500 actcgagccg gccggagccg cggctaacgt ggtattggca ctcccgtctc gacccagcct 10560 acaaaaatcc aggatacgga atcgagtcgt tttgctggtt tccgaatggc agggaagtga 10620 gtcctatttt ttttttttgc cgctcagatg catcccgtgc tgcgacagat gcgcccccaa 10680 caacagcccc cctcgcagca gcagcagcag caatcacaaa aggctgtccc tgcaactact 10740 gcaactgccg ccgtgagcgg tgcgggacag cccgcctatg atctggactt ggaagagggc 10800 gaaggactgg cacgtctagg tgcgccttca cccgagcggc atccgcgagt tcaactgaaa 10860 aaagattctc gcgaggcgta tgtgccccaa cagaacctat ttagagacag aagcggcgag 10920 gagccggagg agatgcgagc ttcccgcttt aacgcgggtc gtgagctgcg tcacggtttg 10980 gaccgaagac gagtgttgcg ggacgaggat ttcgaagttg atgaaatgac agggatcagt 11040 cctgccaggg cacacgtggc tgcagccaac cttgtatcgg cttacgagca gacagtaaag 11 100 gaagagcgta acttccaaaa gtcttttaat aatcatgtgc gaaccctgat tgcccgcgaa 11160 gaagttaccc ttggtttgat gcatttgtgg gatttgatgg aagctatcat tcagaaccct 11220 actagcaaac ctctgaccgc ccagctgttt ctggtggtgc aacacagcag agacaatgag 11280 gctttcagag aggcgctgct gaacatcacc gaacccgagg ggagatggtt gtatgatctt 11340 atcaacattc tacagagtat catagtgcag gagcggagcc tgggcctggc cgagaaggtg 11400 gctgccatca attactcggt tttgagcttg ggaaaatatt acgctcgcaa aatctacaag 11460 actccatacg ttcccataga caaggaggtg aagatagatg ggttctacat gcgcatgacg 11520 ctcaaggtct tgaccctgag cgatgatctt ggggtgtatc gcaatgacag aatgcatcgc 11580 gcggttagcg ccagcaggag gcgcgagtta agcgacaggg aactgatgca cagtttgcaa 11640 agagctctga ctggagctgg aaccgagggt gagaattact tcgacatggg agctgacttg 11700 cagtggcagc ctagtcgcag ggctctgagc gccgcgacgg caggatgtga gcttccttac 11760 atagaagagg cggatgaagg cgaggaggaa gagggcgagt acttggaaga ctgatggcac 11820 aacccgtgtt ttttgctaga tggaacagca agcaccggat cccgcaatgc gggcggcgct 11880 gcagagccag ccgtccggca ttaactcctc ggacgattgg acccaggcca tgcaacgtat 11940 catggcgttg acgactcgca accccgaagc ctttagacag caaccccagg ccaaccgtct 12000 atcggccatc atggaagctg tagtgccttc ccgctctaat cccactcatg agaaggtcct 12060 ggccatcgtg aacgcgttgg tggagaacaa agctattcgt ccagatgagg ccggactggt 12120 atacaacgct ctcttagaac gcgtggctcg ctacaacagt agcaatgtgc aaaccaattt 12180 ggaccgtatg ataacagatg tacgcgaagc cgtgtctcag cgcgaaaggt tccagcgtga 12240 tgccaacctg ggttcgctgg tggcgttaaa tgctttcttg agtactcagc ctgctaatgt 12300 gccgcgtggt caacaggatt atactaactt tttaagtgct ttgagactga tggtatcaga 12360 agtacctcag agcgaagtgt atcagtccgg tcctgattac ttctttcaga ctagcagaca 12420 gggcttgcag acggtaaatc tgagccaagc ttttaaaaac cttaaaggtt tgtggggagt 12480 gcatgccccg gtaggagaaa gagcaaccgt gtctagcttg ttaactccga actcccgcct 12540 attattactg ttggtagctc ctttcaccga cagcggtagc atcgaccgta attcctattt 12600 gggttaccta ctaaacctgt atcgcgaagc catagggcaa agtcaggtgg acgagcagac 12660 ctatcaagaa attacccaag tcagtcgcgc tttgggacag gaagacactg gcagtttgga 12720 agccactctg aacttcttgc ttaccaatcg gtctcaaaag atccctcctc aatatgctct 12780 tactgcggag gaggagagga tccttagata tgtgcagcag agcgtgggat tgtttctgat 12840 gcaagagggg gcaactccga ctgcagcact ggacatgaca gcgcgaaata tggagcccag 12900 catgtatgcc agtaaccgac ctttcattaa caaactgctg gactacttgc acagagctgc 12960 cgctatgaac tctgattatt tcaccaatgc catcttaaac ccgcactggc tgcccccacc 13020 tggtttctac acgggcgaat atgacatgcc cgaccctaat gacggatttc tgtgggacga 13080 cgtggacagc gatgtttttt cacctctttc tgatcatcgc acgtggaaaa aggaaggcgg 13140 cgatagaatg cattcttctg catcgctgtc cggggtcatg ggtgctaccg cggctgagcc 13200 cgagtctgca agtccttttc ctagtctacc cttttctcta cacagtgtac gtagcagcga 13260 agtgggtaga ataagtcgcc cgagtttaat gggcgaagag gagtatctaa acgattcctt 13320 gctcagaccg gcaagagaaa aaaatttccc aaacaatgga atagaaagtt tggtggataa 13380 aatgagtaga tggaagactt atgctcagga tcacagagac gagcctggga tcatggggat 13440 tacaagtaga gcgagccgta gacgccagcg ccatgacaga cagaggggtc ttgtgtggga 13500 cgatgaggat tcggccgatg atagcagcgt gctggacttg ggtgggagag gaaggggcaa 13560 cccgtttgct catttgcgcc ctcgcttggg tggtatgttg taaaaaaaaa taaaaaaaaa 13620 actcaccaag gccatggcga cgagcgtacg ttcgttcttc tttattatct gtgtctagta 13680 taatgaggcg agtcgtgcta ggcggagcgg tggtgtatcc ggagggtcct cctccttcgt 13740 acgagagcgt gatgcagcag cagcaggcga cggcggtgat gcaatcccca ctggaggctc 13800 cctttgtgcc tccgcgatac ctggcaccta cggagggcag aaacagcatt cgttattcgg 13860 aactggcacc tcagtacgat accaccaggt tgtatctggt ggacaacaag tcggcggaca 13920 ttgcttctct gaactatcag aatgaccaca gcaacttctt gaccacggtg gtgcaaaaca 13980 atgactttac ccctacggaa gccagcaccc agaccattaa ctttgatgaa cgatcgcggt 14040 ggggcggtca gctaaagacc atcatgcata ctaacatgcc aaacgtgaac gagtatatgt 14100 ttagtaacaa gttcaaagcg cgtgtgatgg tgtccagaaa acctcccgac ggtgctgcag 14160 ttggggatac ttatgatcac aagcaggata ttttgaaata tgagtggttc gagtttactt 14220 tgccagaagg caacttttca gttactatga ctattgattt gatgaacaat gccatcatag 14280 ataattactt gaaagtgggt agacagaatg gagtgcttga aagtgacatt ggtgttaagt 14340 tcgacaccag gaacttcaag ctgggatggg atcccgaaac caagttgatc atgcctggag 14400 tgtatacgta tgaagccttc catcctgaca ttgtcttact gcctggctgc ggagtggatt 14460 ttaccgagag tcgtttgagc aaccttcttg gtatcagaaa aaaacagcca tttcaagagg 14520 gttttaagat tttgtatgaa gatttagaag gtggtaatat tccggccctc ttggatgtag 14580 atgcctatga gaacagtaag aaagaacaaa aagccaaaat agaagctgct acagctgctg 14640 cagaagctaa ggcaaacata gttgccagcg actctacaag ggttgctaac gctggagagg 14700 tcagaggaga caattttgcg ccaacacctg ttccgactgc agaatcatta ttggccgatg 14760 tgtctgaagg aacggacgtg aaactcacta ttcaacctgt agaaaaagat agtaagaata 14820 gaagctataa tgtgttggaa gacaaaatca acacagccta tcgcagttgg tatctttcgt 14880 acaattatgg cgatcccgaa aaaggagtgc gttcctggac attgctcacc acctcagatg 14940 tcacctgcgg agcagagcag gtctactggt cgcttccaga catgatgaag gatcctgtca 15000 ctttccgctc cactagacaa gtcagtaact accctgtggt gggtgcagag cttatgcccg 15060 tcttctcaaa gagcttctac aacgaacaag ctgtgtactc ccagcagctc cgccagtcca 15120 cctcgcttac gcacgtcttc aaccgctttc ctgagaacca gattttaatc cgtccgccgg 15180 cgcccaccat taccaccgtc agtgaaaacg ttcctgctct cacagatcac gggaccctgc 15240 cgttgcgcag cagtatccgg ggagtccaac gtgtgaccgt tactgacgcc agacgccgca 15300 cctgtcccta cgtgtacaag gcactgggca tagtcgcacc gcgcgtcctt tcaagccgca 15360 ctttctaaaa aaaaaaaaaa tgtccattct tatctcgccc agtaataaca ccggttgggg 15420 tctgcgcgct ccaagcaaga tgtacggagg cgcacgcaaa cgttctaccc aacatcctgt 15480 ccgtgttcgc ggacattttc gcgctccatg gggcgccctc aagggccgca ctcgcgttcg 15540 aaccaccgtc gatgatgtaa tcgatcaggt ggttgccgac gcccgtaatt atactcctac 15600 tgcgcctaca tctactgtgg atgcagttat tgacagtgta gtggctgacg ctcgcaacta 15660 tgctcgacgt aagagccggc gaaggcgcat tgccagacgc caccgagcta ccactgccat 15720 gcgagccgca agagctctgc tacgaagagc tagacgcgtg gggcgaagag ccatgcttag 15780 ggcggccaga cgtgcagctt cgggcgccag cgccggcagg tcccgcaggc aagcagccgc 15840 tgtcgcagcg gcgactattg ccgacatggc ccaatcgcga agaggcaatg tatactgggt 15900 gcgtgacgct gccaccggtc aacgtgtacc cgtgcgcacc cgtccccctc gcacttagaa 15960 gatactgagc agtctccgat gttgtgtccc agcggcgagg atgtccaagc gcaaatacaa 16020 ggaagaaatg ctgcaggtta tcgcacctga agtctacggc caaccgttga aggatgaaaa 16080 aaaaccccgc aaaatcaagc gggttaaaaa ggacaaaaaa gaagaggaag atggcgatga 16140 tgggctggcg gagtttgtgc gcgagtttgc cccacggcga cgcgtgcaat ggcgtgggcg 16200 caaagttcga catgtgttga gacctggaac ttcggtggtc tttacacccg gcgagcgttc 16260 aagcgctact tttaagcgtt cctatgatga ggtgtacggg gatgatgata ttcttgagca 16320 ggcggctgac cgattaggcg agtttgctta tggcaagcgt agtagaataa cttccaagga 16380 tgagacagtg tcgataccct tggatcatgg aaatcccacc cctagtctta aaccggtcac 16440 tttgcagcaa gtgttacccg taactccgcg aacaggtgtt aaacgcgaag gtgaagattt 16500 gtatcccact atgcaactga tggtacccaa acgccagaag ttggaggacg ttttggagaa 16560 agtaaaagtg gatccagata ttcaacctga ggttaaagtg agacccatta agcaggtagc 16620 gcctggtctg ggggtacaaa ctgtagacat taagattccc actgaaagta tggaagtgca 16680 aactgaaccc gcaaagccta ctgccacctc cactgaagtg caaacggatc catggatgcc 16740 catgcctatt acaactgacg ccgccggtcc cactcgaaga tcccgacgaa agtacggtcc 16800 agcaagtctg ttgatgccca attatgttgt acacccatct attattccta ctcctggtta 16860 ccgaggcact cgctactatc gcagccgaaa cagtacctcc cgccgtcgcc gcaagacacc 16920 tgcaaatcgc agtcgtcgcc gtagacgcac aagcaaaccg actcccggcg ccctggtgcg 16980 gcaagtgtac cgcaatggta gtgcggaacc tttgacactg ccgcgtgcgc gttaccatcc 17040 gagtatcatc acttaatcaa tgttgccgct gcctccttgc agatatggcc ctcacttgtc 17100 gccttcgcgt tcccatcact ggttaccgag gaagaaactc gcgccgtaga agagggatgt 17160 tgggacgcgg aatgcgacgc tacaggcgac ggcgtgctat ccgcaagcaa ttgcggggtg 17220 gttttttacc agccttaatt ccaattatcg ctgctgcaat tggcgcgata ccaggcatag 17280 cttccgtggc ggttcaggcc tcgcaacgac attgacattg gaaaaaaacg tataaataaa 17340 aaaaaaaaaa tacaatggac tctgacactc ctggtcctgt gactatgttt tcttagagat 17400 ggaagacatc aatttttcat ccttggctcc gcgacacggc acgaagccgt acatgggcac 17460 ctggagcgac atcggcacga gccaactgaa cgggggcgcc ttcaattgga gcagtatctg 17520 gagcgggctt aaaaattttg gctcaaccat aaaaacatac gggaacaaag cttggaacag 17580 cagtacagga caggcgctta gaaataaact taaagaccag aacttccaac aaaaagtagt 17640 cgatgggata gcttccggca tcaatggagt ggtagatttg gctaaccagg ctgtgcagaa 17700 aaagataaac agtcgtttgg acccgccgcc agcaacccca ggtgaaatgc aagtggagga 17760 agaaattcct ccgccagaaa aacgaggcga caagcgtccg cgtcccgatt tggaagagac 17820 gctggtgacg cgcgtagatg aaccgccttc ttatgaggaa gcaacgaagc ttggaatgcc 17880 caccactaga ccgatagccc caatggccac cggggtgatg aaaccttctc agttgcatcg 17940 acccgtcacc ttggatttgc cccctccccc tgctgctact gctgtacccg cttctaagcc 18000 tgtcgctgcc ccgaaaccag tcgccgtagc caggtcacgt cccgggggcg ctcctcgtcc 18060 aaatgcgcac tggcaaaata ctctgaacag catcgtgggt ctaggcgtgc aaagtgtaaa 18 120 acgccgtcgc tgcttttaat taaatatgga gtagcgctta acttgcctat ctgtgtatat 18180 gtgtcattac acgccgtcac agcagcagag gaaaaaagga agaggtcgtg cgtcgacgct 18240 gagttacttt caagatggcc accccatcga tgctgcccca atgggcatac atgcacatcg 18300 ccggacagga tgcttcggag tacctgagtc cgggtctggt gcagttcgcc cgcgccacag 18360 acacctactt caatctggga aataagttta gaaatcccac cgtagcgccg acccacgatg 18420 tgaccaccga ccgtagccag cggctcatgt tgcgcttcgt gcccgttgac cgggaggaca 18480 atacatactc ttacaaagtg cggtacaccc tggccgtggg cgacaacaga gtgctggata 18540 tggccagcac gttctttgac attaggggtg tgttggacag aggtcccagt ttcaaaccct 18600 attctggtac ggcttacaac tccctggctc ctaaaggcgc tccaaataca tctcagtgga 18660 ttgcagaagg tgtaaaaaat acaactggtg aggaacacgt aacagaagag gaaaccaata 18720 ctactactta cacttttggc aatgctcctg taaaagctga agctgaaatt acaaaagaag 18780 gactcccagt aggtttggaa gtttcagatg aagaaagtaa accgatttat gctgataaaa 18840 catatcagcc agaacctcag ctgggagatg aaacttggac tgaccttgat ggaaaaaccg 18900 aaaagtatgg aggcagggct ctcaaacccg atactaagat gaaaccatgc tacgggtcct 18960 ttgccaaacc tactaatgtg aaaggcggtc aggcaaaaca aaaaacaacg gagcagccaa 19020 atcagaaagt cgaatatgat atcgacatgg agttttttga tgcggcatcg cagaaaacaa 19080 acttaagtcc taaaattgtc atgtatgcag aaaatgtaaa tttggaaact ccagacactc 19140 atgtagtgta caaacctgga acagaagaca caagttccga agctaatttg ggacaacaat 19200 ctatgcccaa cagacccaac tacattggct tcagagataa ctttattgga cttatgtact 19260 ataacagtac tggtaacatg ggggtgctgg ctggtcaagc gtctcagtta aatgcagtgg 19320 ttgacttgca ggacagaaac acagaacttt cttaccaact cttgcttgac tctctgggcg 19380 acagaaccag atactttagc atgtggaatc aggctgtgga cagttatgat cctgatgtac 19440 gtgttattga aaatcatggt gtggaagatg aacttcccaa ctactgtttt ccactggacg 19500 gcataggtgt tccaacaacc agttacaaat caatagttcc aaatggagac aatgcgccta 19560 attggaagga acctgaagta aatggaacaa gtgagatcgg acagggtaat ttgtttgcca 19620 tggaaattaa ccttcaagcc aatctatggc gaagtttcct ttattccaat gtggctctat 19680 atctcccaga ctcgtacaaa tacaccccgt ccaatgtcac tcttccagaa aacaaaaaca 19740 cctacgacta catgaacggg cgggtggtgc cgccatctct agtagacacc tatgtgaaca 19800 ttggtgccag gtggtctctg gatgccatgg acaatgtcaa cccattcaac caccaccgta 19860 acgctggctt gcgttaccga tccatgcttc tgggtaacgg acgttatgtg cctttccaca 19920 tacaagtgcc tcaaaaattc ttcgctgtta aaaacctgct gcttctccca ggctcctaca 19980 cttatgagtg gaactttagg aaggatgtga acatggttct acagagttcc ctcggtaacg 20040 acctgcgggt agatggcgcc agcatcagtt tcacgagcat caacctctat gctacttttt 20100 tccccatggc tcacaacacc gcttccaccc ttgaagccat gctgcggaat gacaccaatg 20160 atcagtcatt caacgactac ctatctgcag ctaacatgct ctaccccatt cctgccaatg 20220 caaccaatat tcccatttcc attccttctc gcaactgggc ggctttcaga ggctggtcat 20280 ttaccagact gaaaaccaaa gaaactccct ctttggggtc tggatttgac ccctactttg 20340 tctattctgg ttctattccc tacctggatg gtaccttcta cctgaaccac acttttaaga 20400 aggtttccat catgtttgac tcttcagtga gctggcctgg aaatgacagg ttactatctc 20460 ctaacgaatt tgaaataaag cgcactgtgg atggcgaagg ctacaacgta gcccaatgca 20520 acatgaccaa agactggttc ttggtacaga tgctcgccaa ctacaacatc ggctatcagg 20580 gcttctacat tccagaagga tacaaagatc gcatgtattc atttttcaga aacttccagc 20640 ccatgagcag gcaggtggtt gatgaggtca attacaaaga cttcaaggcc gtcgccatac 20700 cctaccaaca caacaactct ggctttgtgg gttacatggc tccgaccatg cgccaaggtc 20760 aaccctatcc cgctaactat ccctatccac tcattggaac aactgccgta aatagtgtta 20820 cgcagaaaaa gttcttgtgt gacagaacca tgtggcgcat accgttctcg agcaacttca 20880 tgtctatggg ggcccttaca gacttgggac agaatatgct ctatgccaac tcagctcatg 20940 ctctggacat gacctttgag gtggatccca tggatgagcc caccctgctt tatcttctct 21000 tcgaagtttt cgacgtggtc agagtgcatc agccacaccg cggcatcatc gaggcagtct 21060 acctgcgtac accgttctcg gccggtaacg ctaccacgta agaagcttct tgcttcttgc 21120 aaatagcagc tgcaaccatg gcctgcggat cccaaaacgg ctccagcgag caagagctca 21180 gagccattgt ccaagacctg ggttgcggac cctatttttt gggaacctac gataagcgct 21240 tcccggggtt catggccccc gataagctcg cctgtgccat tgtaaatacg gccggacgtg 21300 agacgggggg agagcactgg ttggctttcg gttggaaccc acgttctaac acctgctacc 21360 tttttgatcc ttttggattc tcggatgatc gtctcaaaca gatttaccag tttgaatatg 21420 agggtctcct gcgccgcagc gctcttgcta ccaaggaccg ctgtattacg ctggaaaaat 21480 ctacccagac cgtgcagggt ccccgttctg ccgcctgcgg acttttctgc tgcatgttcc 21540 ttcacgcctt tgtgcactgg cctgaccgtc ccatggacgg aaaccccacc atgaaattgc 21600 taactggagt gccaaacaac atgcttcatt ctcctaaagt ccagcccacc ctgtgtgaca 21660 atcaaaaagc actctaccat tttcttaata cccattcgcc ttattttcgc tcccatcgta 21720 cacacatcga aagggccact gcgttcgacc gtatggatgt tcaataatga ctcatgtaaa 21780 caacgtgttc aataaacatc actttatttt tttacatgta tcaaggctct gcattactta 21840 tttatttaca agtcgaatgg gttctgacga gaatcagaat gacccgcagg cagtgatacg 21900 ttgcggaact gatacttggg ttgccacttg aattcgggaa tcaccaactt gggaaccggt 21960 atatcgggca ggatgtcact ccacagcttt ctggtcagct gcaaagctcc aagcaggtca 22020 ggagccgaaa tcttgaaatc acaattagga ccagtgcttt gagcgcgaga gttgcggtac 22080 accggattgc agcactgaaa caccatcagc gacggatgtc tcacgcttgc cagcacggtg 22140 ggatctgcaa tcatgcccac atccagatct tcagcattgg caatgctgaa cggggtcatc 22200 ttgcaggtct gcctacccat ggcgggcacc caattaggct tgtggttgca atcgcagtgc 22260 agggggatca gtatcatctt ggcctgatcc tgtctgattc ctggatacac ggctctcatg 22320 aaagcatcat attgcttgaa agcctgctgg gctttactac cctcggtata aaacatcccg 22380 caggacctgc tcgaaaactg gttagctgca cagccggcat cattcacaca gcagcgggcg 22440 tcattgttag ctatttgcac cacacttctg ccccagcggt tttgggtgat tttggttcgc 22500 tcgggattct cctttaaggc tcgttgtccg ttctcgctgg ccacatccat ctcgataatc 22560 tgctccttct gaatcataat attgccatgc aggcacttca gcttgccctc ataatcattg 22620 cagccatgag gccacaacgc acagcctgta cattcccaat tatggtgggc gatctgagaa 22680 aaagaatgta tcattccctg cagaaatctt cccatcatcg tgctcagtgt cttgtgacta 22740 gtgaaagtta actggatgcc tcggtgctcc tcgtttacgt actggtgaca gatgcgcttg 22800 tattgttcgt gttgctcagg cattagttta aaagaggttc taagttcgtt atccagcctg 22860 tacttctcca tcagcagaca catcacttcc atgcctttct cccaagcaga caccaggggc 22920 aagctaatcg gattcttaac agtgcaggca gcagctcctt tagccagagg gtcatcttta 22980 gcgatcttct caatgcttct tttgccatcc ttctcaacga tgcgcacggg cgggtagctg 23040 aaacccactg ctacaagttg cgcctcttct ctttcttctt cgctgtcttg actgatgtct 23100 tgcatgggga tatgtttggt cttccttggc ttctttttgg ggggtatcgg aggaggagga 23160 ctgtcgctcc gttccggaga cagggaggat tgtgacgttt cgctcaccat taccaactga 23220 ctgtcggtag aagaacctga ccccacacgg cgacaggtgt ttctcttcgg gggcagaggt 23280 ggaggcgatt gcgaagggct gcggtccgac ctggaaggcg gatgactggc agaacccctt 23340 ccgcgttcgg gggtgtgctc cctgtggcgg tcgcttaact gatttccttc gcggctggcc 23400 attgtgttct cctaggcaga gaaacaacag acatggaaac tcagccattg ctgtcaacat 23460 cgccacgagt gccatcacat ctcgtcctca gcgacgagga aaaggagcag agcttaagca 23520 ttccaccgcc cagtcctgcc accacctcta ccctagaaga taaggaggtc gacgcatctc 23580 atgacatgca gaataaaaaa gcgaaagagt ctgagacaga catcgagcaa gacccgggct 23640 atgtgacacc ggtggaacac gaggaagagt tgaaacgctt tctagagaga gaggatgaaa 23700 actgcccaaa acaacgagca gataactatc accaagatgc tggaaatagg gatcagaaca 23760 ccgactacct catagggctt gacggggaag acgcgctcct taaacatcta gcaagacagt 23820 cgctcatagt caaggatgca ttattggaca gaactgaagt gcccatcagt gtggaagagc 23880 tcagccgcgc ctacgagctt aacctctttt cacctcgtac tccccccaaa cgtcagccaa 23940 acggcacctg cgagccaaat cctcgcttaa acttttatcc agcttttgct gtgccagaag 24000 tactggctac ctatcacatc ttttttaaaa atcaaaaaat tccagtctcc tgccgcgcta 24060 atcgcacccg cgccgatgcc ctactcaatc tgggacctgg ttcacgctta cctgatatag 24120 cttccttgga agaggttcca aagatcttcg agggtctggg caataatgag actcgggccg 24180 caaatgctct gcaaaaggga gaaaatggca tggatgagca tcacagcgtt ctggtggaat 24 240 tggaaggcga taatgccaga ctcgcagtac tcaagcgaag catcgaggtc acacacttcg 24300 catatcccgc tgtcaacctg ccccctaaag tcatgacggc ggtcatggac cagttactca 24360 ttaagcgcgc aagtcccctt tcagaagaca tgcatgaccc agatgcctgt gatgagggta 24420 aaccagtggt cagtgatgag cagctaaccc gatggctggg caccgactct cccagggatt 24480 tggaagagcg tcgcaagctt atgatggccg tggtgctggt taccgtagaa ctagagtgtc 24540 tccgacgttt ctttaccgat tcagaaacct tgcgcaaact cgaagagaat ctgcactaca 24600 cttttagaca cggctttgtg cggcaggcat gcaagatatc taacgtggaa ctcaccaacc 24660 tggtttccta catgggtatt ctgcatgaga atcgcctagg acaaagcgtg ctgcacagca 24720 ccctgaaggg ggaagcccgc cgtgattaca tccgcgattg tgtctatctg tacctgtgcc 24780 acacgtggca aaccggcatg ggtgtatggc agcaatgttt agaagaacag aacttgaaag 24840 agcttgacaa gctcttacag aaatctctta aggttctgtg gacagggttc gacgagcgca 24900 ccgtcgcttc cgacctggca gacctcatct tcccagagcg tctcagggtt actttgcgaa 24960 acggattgcc tgactttatg agccagagca tgcttaacaa ttttcgctct ttcatcctgg 25020 aacgctccgg tatcctgccc gccacctgct gcgcactgcc ctccgacttt gtgcctctca 25080 cctaccgcga gtgccccccg ccgctatgga gtcactgcta cctgttccgt ctggccaact 25 140 atctctccta ccactcggat gtgatcgagg atgtgagcgg agacggcttg ctggagtgtc 25200 actgccgctg caatctgtgc acgccccacc ggtccctagc ttgcaacccc cagttgatga 25260 gcgaaaccca gataataggc acctttgaat tgcaaggccc cagcagccaa ggcgatgggt 25320 cttctcctgg gcaaagttta aaactgaccc cgggactgtg gacctccgcc tacttgcgca 25380 agtttgctcc ggaagattac cacccctatg aaatcaagtt ctatgaggac caatcacagc 25440 ctccaaaggc cgaactttcg gcctgcgtca tcacccaggg ggcaattctg gcccaattgc 25500 aagccatcca aaaatcccgc caagaatttc tactgaaaaa gggtaagggg gtctaccttg 25560 acccccagac cggcgaggaa ctcaacacaa ggttccctca ggatgtccca acgacgagaa 25620 aacaagaagt tgaaggtgca gccgccgccc ccagaagata tggaggaaga ttgggacagt 25680 caggcagagg aggcggagga ggacagtctg gaggacagtc tggaggaaga cagtttggag 25740 gaggaaaacg aggaggcaga ggaggtggaa gaagtaaccg ccgacaaaca gttatcctcg 25800 gctgcggaga caagcaacag cgctaccatc tccgctccga gtcgaggaac ccggcggcgt 25860 cccagcagta gatgggacga gaccggacgc ttcccgaacc caaccagcgc ttccaagacc 25920 ggtaagaagg atcggcaggg atacaagtcc tggcgggggc ataagaatgc catcatctcc 25980 tgcttgcatg agtgcggggg caacatatcc ttcacgcggc gctacttgct attccaccat 26040 ggggtgaact ttccgcgcaa tgttttgcat tactaccgtc acctccacag cccctactat 26100 agccagcaaa tcccggcagt ctcgacagat aaagacagcg gcggcgacct ccaacagaaa 26160 accagcagcg gcagttagaa aatacacaac aagtgcagca acaggaggat taaagattac 26220 agccaacgag ccagcgcaaa cccgagagtt aagaaatcgg atctttccaa ccctgtatgc 26280 catcttccag cagagtcggg gtcaagagca ggaactgaaa ataaaaaacc gatctctgcg 26340 ttcgctcacc agaagttgtt tgtatcacaa gagcgaagat caacttcagc gcactctcga 26400 ggacgccgag gctctcttca acaagtactg cgcgctgact cttaaagagt aggcagcgac 26460 cgcgcttatt caaaaaaggc gggaattaca tcatcctcga catgagtaaa gaaattccca 26520 cgccttacat gtggagttat caaccccaaa tgggattggc ggcaggcgcc tcccaggact 26580 actccacccg catgaattgg ctcagcgccg ggccttctat gatttctcga gttaatgata 26640 tacgcgccta ccgaaaccaa atacttttgg aacagtcagc tcttaccacc acgccccgcc 26700 aacaccttaa tcccagaaat tggcccgccg ccctagtgta ccaggaaagt cccgctccca 26760 ccactgtatt acttcctcga gacgcccagg ccgaagtcca aatgactaat gcaggtgcgc 26820 agttagctgg cggctccacc ctatgtcgtc acaggcctcg gcataatata aaacgcctga 26880 tgatcagagg ccgaggtatc cagctcaacg acgagtcggt gagctctccg cttggtctac 26940 gaccagacgg aatctttcag attgccggct gcgggagatc ttccttcacc cctcgtcagg 27000 ctgttctgac tttggaaagt tcgtcttcgc aaccccgctc gggcggaatc gggaccgttc 27060 aatttgtgga ggagtttact ccctctgtct acttcaaccc cttctccgga tctcctgggc 27120 attacccgga cgagttcata ccgaacttcg acgcgattag cgagtcagtg gacggctacg 27180 attgatgtct ggtgacgcgg ctgagctatc tcggctgcga catctagacc actgccgccg 27240 ctttcgctgc tttgcccggg aactcattga gttcatctac ttcgaactcc ccaaggatca 27300 ccctcaaggt ccggcccacg gagtgcggat ttctatcgaa ggcaaaatag actctcgcct 27360 gcaacgaatt ttctcccagc ggcccgtgct gatcgagcga gaccagggaa acaccacggt 27420 ttccatctac tgcatttgta atcaccccgg attgcatgaa agcctttgct gtcttatgtg 27480 tactgagttt aataaaaact gaattaagac tctcctacgg actgccgctt cttcaacccg 27540 gattttacaa ccagaagaac gaaacttttc ctgtcgtcca ggactctgtt aacttcacct 27600 ttcctactca caaactagaa gctcaacgac tacaccgctt ttccagaagc attttcccta 27660 ctaatactac tttcaaaacc ggaggtgagc tccaaggtct tcctacagaa aacccttggg 27720 tggaagcggg ccttgtagtg ctaggaattc ttgcgggtgg gcttgtgatt attctttgct 27780 acctatacac accttgcttc actttcttag tggtgttgtg gtattggttt aaaaaatggg 27840 gcccatacta gtcttgcttg ttttactttc gcttttggaa ccgggttctg ccaattacga 27900 tccatgtcta gacttcgacc cagaaaactg cacacttact tttgcacccg acacaagccg 27960 catctgtgga gttcatcgcc tctcttacga acttggcccc caacgacaaa aatttacctg 28020 catggtggga atcaacccca tagttatcac ccagcaaagt ggagatacta agggttgcat 28080 tcactgctcc tgcgattcca tcgagtgcac ctacaccctg ctgaagaccc tatgcggcct 28140 aagagacctg ctaccaatga attaaaaaat gattaataaa aaatcactta cttgaaatca 28200 gcaataaggt ctctgttgaa attttctccc agcagcacct cacttccctc ttcccaactc 28260 tggtattcta aaccccgttc agcggcatac tttctccata ctttaaaggg gatgtcaaat 28320 tttagctcct ctcctgtacc cacaatcttc atgtctttct tcccagatga ccaagagagt 28380 ccggctcagt gactccttca accctgtcta cccctatgaa gatgaaagca cctcccaaca 28440 cccctttata aacccagggt ttatttcccc aaatggcttc acacaaagcc caaacggagt 28500 tcttacttta aaatgtttaa ccccactaac aaccacaggc ggatctctac agctaaaagt 28560 gggaggggga cttacagtgg atgacaccaa cggttttttg aaagaaaaca taagtgccac 28620 cacaccactc gttaagactg gtcactctat aggtttacca ctaggagccg gattgggaac 28680 gaatgaaaat aaactttgta tcaaattagg acaaggactt acattcaatt caaacaacat 28740 ttgcattgat gacaatatta acaccttatg gacaggagtc aaccccaccg aagccaactg 28800 tcaaatcatg aactccagtg aatctaatga ttgcaaatta attctaacac tagttaaaac 28860 tggagcacta gtcactgcat ttgtttatgt tataggagta tctaacaatt ttaatatgct 28920 aactacacac agaaatataa attttactgc agagctgttt ttcgattcta ctggtaattt 28980 actaactaga ctctcatccc tcaaaactcc acttaatcat aaatcaggac aaaacatggc 29040 tactggtgcc attactaatg ctaaaggttt catgcccagc acgactgcct atcctttcaa 29100 tgataattct agagaaaaag aaaactacat ttacggaact tgttactaca cagctagtga 29160 tcgcactgct tttcccattg acatatctgt catgcttaac cgaagagcaa taaatgacga 29220 gacatcatat tgtattcgta taacttggtc ctggaacaca ggagatgccc cagaggtgca 29280 aacctctgct acaaccctag tcacctcccc atttaccttt tactacatca gagaagacga 29340 ctgacaaata aagtttgcga tcgccaggcc accatggcct tgacctttgc tttactggtg 29400 gccctcctgg tgctcagctg caagtcaagc tgctctgtgg gctgtgatct gcctcaaacc 29460 cacagcctgg gtagcaggag gaccttgatg ctcctggcac agatgaggag aatctctctt 29520 ttctcctgct tgaaggacag acatgacttt ggatttcccc aggaggagtt tggcaaccag 29580 ttccaaaagg ctgaaaccat ccctgtcctc catgagatga tccagcagat cttcaatctc 29640 ttcagcacaa aggactcatc tgctgcttgg gatgagaccc tcctagacaa attctacact 29700 gaactctacc agcagctgaa tgacctggaa gcctgtgtga tacagggggt gggggtgaca 29760 gagactcccc tgatgaagga ggactccatt ctggctgtga ggaaatactt ccaaagaatc 29820 actctctatc tgaaagagaa gaaatacagc ccttgtgcct gggaggttgt cagagcagaa 29880 atcatgagat ctttttcttt gtcaacaaac ttgcaagaaa gtttaagaag taaggaagga 29940 agcggagcta ctaacttcag cctgctgaag caggctggag acgtggagga gaaccctgga 30000 cctggccaca cacggaggca gggaacatca ccatccaagt gtccatacct caatttcttt 30060 cagctcttgg tgctggctgg tctttctcac ttctgttcag gtgttatcca cgtgaccaag 30120 gaagtgaaag aagtggcaac gctgtcctgt ggtcacaatg tttctgttga agagctggca 30180 caaactcgca tctactggca aaaggagaag aaaatggtgc tgactatgat gtctggggac 30240 atgaatatat ggcccgagta caagaaccgg accatctttg atatcactaa taacctctcc 30300 attgtgatcc tggctctgcg cccatctgac gagggcacat acgagtgtgt tgttctgaag 30360 tatgaaaaag acgctttcaa gcgggaacac ctggctgaag tgacgttatc agtcaaagct 30420 gacttcccta cacctagtat atctgacttt gaaattccaa cttctaatat tagaaggata 30480 atttgctcaa cctctggagg ttttccagag cctcacctct cctggttgga aaatggagaa 30540 gaattaaatg ccatcaacac aacagtttcc caagatcctg aaactgagct ctatgctgtt 30600 agcagcaaac tggatttcaa tatgacaacc aaccacagct tcatgtgtct catcaagtat 30660 ggacatttaa gagtgaatca gaccttcaac tggaatacaa ccaagcaaga gcattttcct 30720 gataacctgc tcccatcctg ggccattacc ttaatctcag taaatggaat ttttgtgata 30780 tgctgcctga cctactgctt tgccccaaga tgcagagaga gaaggaggaa tgagagattg 30840 agaagggaaa gtgtacgccc tgtataagct agcttgactg actgagatac agcgtacctt 30900 cagctcacag acatgataag atacattgat gagtttggac aaaccacaac tagaatgcag 30960 tgaaaaaaat gctttatttg tgaaatttgt gatgctattg ctttatttgt aaccattata 31020 agctgcaata aacaagttaa caacaacaat tgcattcatt ttatgtttca ggttcagggg 31080 gaggtgtggg aggtttttta aagcaagtaa aacctctaca aatgtggtag tcgtcagcta 31140 tcctgcagga acttgtttat ttgaaaatca attcacaaaa tccgagtagt tattttgcct 31200 cccccttccc atttaacaga atacaccaat ctctccccac gcacagcttt aaacatttgg 31260 ataccattag atatagacat ggttttagat tccacattcc aaacagtttc agagcgagcc 31320 aatctggggt cagtgataga taaaaatcca tcgggatagt cttttaaagc gctttcacag 31380 tccaactgct gcggatgcga ctccggagtc tggatcacgg tcatctggaa gaagaacgat 31440 gggaatcata atccgaaaac ggtatcggac gattgtgtct catcaaaccc acaagcagcc 31500 gctgtctgcg tcgctccgtg cgactgctgt ttatgggatc agggtccaca gtgtcctgaa 31560 gcatgatttt aatagccctt aacatcaact ttctggtgcg atgcgcgcag caacgcattc 31620 tgatttcact caaatctttg cagtaggtac aacacattat tacaatattg tttaataaac 31680 cataattaaa agcgctccag ccaaaactca tatctgatat aatcgcccct gcatgaccat 31740 cataccaaag tttaatataa attaaatgac gttccctcaa aaacacacta cccacataca 31800 tgatctcttt tggcatgtgc atattaacaa tctgtctgta ccatggacaa cgttggttaa 31860 tcatgcaacc caatataacc ttccggaacc acactgccaa caccgctccc ccagccatgc 31920 attgaagtga accctgctga ttacaatgac aatgaagaac ccaattctct cgaccgtgaa 31980 tcacttgaga atgaaaaata tctatagtgg cacaacatag acataaatgc atgcatcttc 32040 tcataatttt taactcctca ggatttagaa acatatccca gggaatagga agctcttgca 32 100 gaacagtaaa gctggcagaa caaggaagac cacgaacaca acttacacta tgcatagtca 32160 tagtatcaca atctggcaac agcgggtggt cttcagtcat agaagctcgg gtttcatttt 32220 cctcacaacg tggtaactgg gctctggtgt aagggtgatg tctggcgcat gatgtcgagc 32280 gtgcgcgcaa ccttgtcata atggagttgc ttcctgacat tctcgtattt tgtatagcaa 32340 aacgcggccc tggcagaaca cactcttctt cgccttctat cctgccgctt agcgtgttcc 32400 gtgtgatagt tcaagtacaa ccacactctt aagttggtca aaagaatgct ggcttcagtt 32460 gtaatcaaaa ctccatcgca tctaatcgtt ctgaggaaat catccaagca atgcaactgg 32520 attgtgtttc aagcaggaga ggagagggaa gagacggaag aaccatgtta atttttattc 32580 caaacgatct cgcagtactt caaattgtag atcgcgcaga tggcatctct cgcccccact 32640 gtgttggtga aaaagcacag ctagatcaaa agaaatgcga ttttcaaggt gctcaacggt 32700 ggcttccagc aaagcctcca cgcgcacatc caagaacaaa agaataccaa aagaaggagc 32760 attttctaac tcctcaatca tcatattaca ttcctgcacc attcccagat aattttcagc 32820 tttccagcct tgaattattc gtgtcagttc ttgtggtaaa tccaatccac acattacaaa 32880 caggtcccgg agggcgccct ccaccaccat tcttaaacac accctcataa tgacaaaata 32940 tcttgctcct gtgtcacctg tagcgaattg agaatggcaa catcaattga catgcccttg 33000 gctctaagtt cttctttaag ttctagttgt aaaaactctc tcatattatc accaaactgc 33060 ttagccagaa gccccccggg aacaagagca ggggacgcta cagtgcagta caagcgcaga 33 120 cctccccaat tggctccagc aaaaacaaga ttggaataag catattggga accgccagta 33180 atatcatcga agttgctgga aatataatca ggcagagttt cttgtaaaaa ttgaataaaa 33240 gaaaaatttg ccaaaaaaac attcaaaacc tctgggatgc aaatgcaata ggttaccgcg 33300 ctgcgctcca acattgttag ttttgaatta gtctgcaaaa ataaaaaaaa aaacaagcgt 33360 catatcatag tagcctgacg aacagatgga taaatcagtc tttccatcac aagacaagcc 33420 acagggtctc cagctcgacc ctcgtaaaac ctgtcatcat gattaaacaa cagcaccgaa 33480 agttcctcgc ggtgaccagc atgaataatt cttgatgaag catacaatcc agacatgtta 33540 gcatcagtta acgagaaaaa acagccaaca tagcctttgg gtataattat gcttaatcgt 33600 aagtatagca aagccacccc tcgcggatac aaagtaaaag gcacaggaga ataaaaaata 33660 taattatttc tctgctgctg ttcaggcaac gtcgcccccg gtccctctaa atacacatac 33720 aaagcctcat cagccatggc ttaccagaca aagtacagcg ggcacacaaa gcacaagctc 33780 taaagtgact ctccaacctc tccacaatat atatatacac aagccctaaa ctgacgtaat 33840 gggagtaaag tgtaaaaaat cccgccaaac ccaacacaca ccccgaaact gcgtcaccag 33900 ggaaaagtac agtttcactt ccgcaatccc aacaggcgta acttcctctt tctcacggta 33960 cgtgatatcc cactaacttg caacgtcatt ttcccacggt cgcaccgccc cttttagccg 34020 ttaaccccac agccaatcac cacacgatcc acacttttta aaatcacctc atttacatat 34080 tggcaccatt ccatctataa ggtatattat atagataga 34119 <210> 18 <211> 34131 <212> DNA <213> Artificial Sequence <220> <223> NG-345 virus genome sequence comprising the EnAd genome with a transgene cassette that encodes Flt3 Ligand, MIP1a and IFNa, inserted in the region BY. The transgene cassette contains a 5' SSA, Flt3 Ligand cDNA, P2A peptide sequence, MIP1a cDNA sequence <400> 18 tctatctata taatatacct tatagatgga atggtgccaa tatgtaaatg aggtgatttt 60 aaaaagtgtg gatcgtgtgg tgattggctg tggggttaac ggctaaaagg ggcggtgcga 120 ccgtgggaaa atgacgtttt gtgggggtgg agtttttttg caagttgtcg cgggaaatgt 180 gacgcataaa aaggcttttt tctcacggaa ctacttagtt ttcccacggt atttaacagg 240 aaatgaggta gttttgaccg gatgcaagtg aaaattgttg attttcgcgc gaaaactgaa 300 tgaggaagtg tttttctgaa taatgtggta tttatggcag ggtggagtat ttgttcaggg 360 ccaggtagac tttgacccat tacgtggagg tttcgattac cgtgtttttt acctgaattt 420 ccgcgtaccg tgtcaaagtc ttctgttttt acgtaggtgt cagctgatcg ctagggtatt 480 tatacctcag ggtttgtgtc aagaggccac tcttgagtgc cagcgagaag agttttctcc 540 tctgcgccgg cagtttaata ataaaaaaat gagagatttg cgatttctgc ctcaggaaat 600 aatctctgct gagactggaa atgaaatatt ggagcttgtg gtgcacgccc tgatgggaga 660 cgatccggag ccacctgtgc agctttttga gcctcctacg cttcaggaac tgtatgattt 720 agaggtagag ggatcggagg attctaatga ggaagctgta aatggctttt ttaccgattc 780 tatgctttta gctgctaatg aagggttaga attagatccg cctttggaca cttttgatac 840 tccaggggta attgtggaaa gcggtacagg tgtaagaaaa ttacctgatt tgagttccgt 900 ggactgtgat ttgcactgct atgaagacgg gtttcctccg agtgatgagg aggaccatga 960 aaaggagcag tccatgcaga ctgcagcggg tgagggagtg aaggctgcca atgttggttt 1020 tcagttggat tgcccggagc ttcctggaca tggctgtaag tcttgtgaat ttcacaggaa 1080 aaatactgga gtaaaggaac tgttatgttc gctttgttat atgagaacgc actgccactt 1140 tatttacagt aagtgtgttt aagttaaaat ttaaaggaat atgctgtttt tcacatgtat 1200 attgagtgtg agttttgtgc ttcttattat aggtcctgtg tctgatgctg atgaatcacc 1260 atctcctgat tctactacct cacctcctga gattcaagca cctgttcctg tggacgtgcg 1320 caagcccatt cctgtgaagc ttaagcctgg gaaacgtcca gcagtggaaa aacttgagga 1380 cttgttacag ggtggggacg gacctttgga cttgagtaca cggaaacgtc caagacaata 1440 agtgttccat atccgtgttt acttaaggtg acgtcaatat ttgtgtgaca gtgcaatgta 1500 ataaaaatat gttaactgtt cactggtttt tattgctttt tgggcgggga ctcaggtata 1560 taagtagaag cagacctgtg tggttagctc ataggagctg gctttcatcc atggaggttt 1620 gggccatttt ggaagacctt aggaagacta ggcaactgtt agagaacgct tcggacggag 1680 tctccggttt ttggagattc tggttcgcta gtgaattagc tagggtagtt tttaggataa 1740 aacaggacta taaacaagaa tttgaaaagt tgttggtaga ttgcccagga ctttttgaag 1800 ctcttaattt gggccatcag gttcacttta aagaaaaagt tttatcagtt ttagactttt 1860 caaccccagg tagaactgct gctgctgtgg cttttcttac ttttatatta gataaatgga 1920 tcccgcagac tcatttcagc aggggatacg ttttggattt catagccaca gcattgtgga 1980 gaacatggaa ggttcgcaag atgaggacaa tcttaggtta ctggccagtg cagcctttgg 2040 gtgtagcggg aatcctgagg catccaccgg tcatgccagc ggttctggag gaggaacagc 2100 aagaggacaa cccgagagcc ggcctggacc ctccagtgga ggaggcggag tagctgactt 2160 gtctcctgaa ctgcaacggg tgcttactgg atctacgtcc actggacggg ataggggcgt 2220 taagagggag agggcatcta gtggtactga tgctagatct gagttggctt taagtttaat 2280 gagtcgcaga cgtcctgaaa ccatttggtg gcatgaggtt cagaaagagg gaagggatga 2340 agtttctgta ttgcaggaga aatattcact ggaacaggtg aaaacatgtt ggttggagcc 2400 tgaggatgat tgggaggtgg ccattaaaaa ttatgccaag atagctttga ggcctgataa 2460 acagtataag attactagac ggattaatat ccggaatgct tgttacatat ctggaaatgg 2520 ggctgaggtg gtaatagata ctcaagacaa ggcagttatt agatgctgca tgatggatat 2580 gtggcctggg gtagtcggta tggaagcagt aacttttgta aatgttaagt ttaggggaga 2640 tggttataat ggaatagtgt ttatggccaa taccaaactt atattgcatg gttgtagctt 2700 ttttggtttc aacaatacct gtgtagatgc ctggggacag gttagtgtac ggggatgtag 2760 tttctatgcg tgttggattg ccacagctgg cagaaccaag agtcaattgt ctctgaagaa 2820 atgcatattt caaagatgta acctgggcat tctgaatgaa ggcgaagcaa gggtccgcca 2880 ctgcgcttct acagatactg gatgttttat tttgattaag ggaaatgcca gcgtaaagca 2940 taacatgatt tgcggtgctt ccgatgagag gccttatcaa atgctcactt gtgctggtgg 3000 gcattgtaat atgctggcta ctgtgcatat tgtttcccat caacgcaaaa aatggcctgt 3060 ttttgatcac aatgtgatga cgaagtgtac catgcatgca ggtgggcgta gaggaatgtt 3120 tatgccttac cagtgtaaca tgaatcatgt gaaagtgttg ttggaaccag atgccttttc 3180 cagaatgagc ctaacaggaa tttttgacat gaacatgcaa atctggaaga tcctgaggta 3240 tgatgatacg agatcgaggg tacgcgcatg cgaatgcgga ggcaagcatg ccaggttcca 3300 gccggtgtgt gtagatgtga ctgaagatct cagaccggat catttggtta ttgcccgcac 3360 tggagcagag ttcggatcca gtggagaaga aactgactaa ggtgagtatt gggaaaactt 3420 tggggtggga ttttcagatg gacagattga gtaaaaattt gttttttctg tcttgcagct 3480 gtcatgagtg gaaacgcttc ttttaagggg ggagtcttca gcccttatct gacagggcgt 3540 ctcccatcct gggcaggagt tcgtcagaat gttatgggat ctactgtgga tggaagaccc 3600 gtccaacccg ccaattcttc aacgctgacc tatgctactt taagttcttc acctttggac 3660 gcagctgcag ctgccgccgc cgcttctgtt gccgctaaca ctgtgcttgg aatgggttac 3720 tatggaagca tcatggctaa ttccacttcc tctaataacc cttctaccct gactcaggac 3780 aagttacttg tccttttggc ccagctggag gctttgaccc aacgtctggg tgaactttct 3840 cagcaggtgg tcgagttgcg agtacaaact gagtctgctg tcggcacggc aaagtctaaa 3900 taaaaaaatc ccagaatcaa tgaataaata aacaagcttg ttgttgattt aaaatcaagt 3960 gtttttattt catttttcgc gcacggtatg ccctagacca ccgatctcta tcattgagaa 4020 ctcggtggat tttttccagg atcctataga ggtgggattg aatgtttaga tacatgggca 4080 ttaggccgtc tttggggtgg agatagctcc attgaaggga ttcatgctcc ggggtagtgt 4140 tgtaaatcac ccagtcataa caaggtcgca gtgcatggtg ttgcacaata tcttttagaa 4200 gtaggctgat tgccacagat aagcccttgg tgtaggtgtt tacaaaccgg ttgagctggg 4260 atgggtgcat tcggggtgaa attatgtgca ttttggattg gatttttaag ttggcaatat 4320 tgccgccaag atcccgtctt gggttcatgt tatgaaggac caccaagacg gtgtatccgg 4380 tacatttagg aaatttatcg tgcagcttgg atggaaaagc gtggaaaaat ttggagacac 4440 ccttgtgtcc tccaagattt tccatgcact catccatgat aatagcaatg gggccgtggg 4500 cagcggcgcg ggcaaacacg ttccgtgggt ctgacacatc atagttatgt tcctgagtta 4560 aatcatcata agccatttta atgaatttgg ggcggagagt accagattgg ggtatgaatg 4620 ttccttcggg ccccggagca tagttcccct cacagatttg catttcccaa gctttcagtt 4680 ccgagggtgg aatcatgtcc acctgggggg ctatgaaaaa caccgtttct ggggcggggg 4740 tgattaattg tgatgatagc aaatttctga gcaattgaga tttgccacat ccggtggggc 4800 cataaatgat tccgattacg ggttgcaggt ggtagtttag ggaacggcaa ctgccgtctt 4860 ctcgaagcaa gggggccacc tcgttcatca tttcccttac atgcatattt tcccgcacca 4920 aatccattag gaggcgctct cctcctagtg atagaagttc ttgtagtgag gaaaagtttt 4980 tcagcggttt cagaccgtca gccatgggca ttttggagag agtttgctgc aaaagttcta 5040 gtctgttcca cagttcagtg atgtgttcta tggcatctcg atccagcaga cctcctcgtt 5100 tcgcgggttt ggacggctcc tggaataggg tatgagacga tgggcgtcca gcgctgccag 5160 ggttcggtcc ttccagggtc tcagtgttcg agtcagggtt gtttccgtca cagtgaaggg 5220 gtgtgcgcct gcttgggcgc ttgccagggt gcgcttcaga ctcatcctgc tggtcgaaaa 5280 cttctgtcgc ttggcgccct gtatgtcggc caagtagcag tttaccatga gttcgtagtt 5340 gagcgcctcg gctgcgtggc ctttggcgcg gagcttacct ttggaagttt tcttgcatac 5400 cgggcagtat aggcatttca gcgcatacaa cttgggcgca aggaaaacgg attctgggga 5460 gtatgcatct gcgccgcagg aggcgcaaac agtttcacat tccaccagcc aggttaaatc 5520 cggttcattg gggtcaaaaa caagttttcc gccatatttt ttgatgcgtt tcttaccttt 5580 ggtctccatg agttcgtgtc ctcgttgagt gacaaacagg ctgtccgtgt ccccgtagac 5640 tgattttaca ggcctcttct ccagtggagt gcctcggtct tcttcgtaca ggaactctga 5700 ccactctgat acaaaggcgc gcgtccaggc cagcacaaag gaggctatgt gggaggggta 5760 gcgatcgttg tcaaccaggg ggtccacctt ttccaaagta tgcaaacaca tgtcaccctc 5820 ttcaacatcc aggaatgtga ttggcttgta ggtgtatttc acgtgacctg gggtccccgc 5880 tgggggggta taaaaggggg cggttctttg ctcttcctca ctgtcttccg gatcgctgtc 5940 caggaacgtc agctgttggg gtaggtattc cctctcgaag gcgggcatga cctctgcact 6000 caggttgtca gtttctaaga acgaggagga tttgatattg acagtgccgg ttgagatgcc 6060 tttcatgagg ttttcgtcca tctggtcaga aaacacaatt tttttattgt caagtttggt 6120 ggcaaatgat ccatacaggg cgttggataa aagtttggca atggatcgca tggtttggtt 6180 cttttccttg tccgcgcgct ctttggcggc gatgttgagt tggacatact cgcgtgccag 6240 gcacttccat tcggggaaga tagttgttaa ttcatctggc acgattctca cttgccaccc 6300 tcgattatgc aaggtaatta aatccacact ggtggccacc tcgcctcgaa ggggttcatt 6360 ggtccaacag agcctacctc ctttcctaga acagaaaggg ggaagtgggt ctagcataag 6420 ttcatcggga gggtctgcat ccatggtaaa gattcccgga agtaaatcct tatcaaaata 6480 gctgatggga gtggggtcat ctaaggccat ttgccattct cgagctgcca gtgcgcgctc 6540 atatgggtta aggggactgc cccatggcat gggatgggtg agtgcagagg catacatgcc 6600 acagatgtca tagacgtaga tgggatcctc aaagatgcct atgtaggttg gatagcatcg 6660 cccccctctg atacttgctc gcacatagtc atatagttca tgtgatggcg ctagcagccc 6720 cggacccaag ttggtgcgat tgggtttttc tgttctgtag acgatctggc gaaagatggc 6780 gtgagaattg gaagagatgg tgggtctttg aaaaatgttg aaatgggcat gaggtagacc 6840 tacagagtct ctgacaaagt gggcataaga ttcttgaagc ttggttacca gttcggcggt 6900 gacaagtacg tctagggcgc agtagtcaag tgtttcttga atgatgtcat aacctggttg 6960 gtttttcttt tcccacagtt cgcggttgag aaggtattct tcgcgatcct tccagtactc 7020 ttctagcgga aacccgtctt tgtctgcacg gtaagatcct agcatgtaga actgattaac 7080 tgccttgtaa gggcagcagc ccttctctac gggtagagag tatgcttgag cagcttttcg 7140 tagcgaagcg tgagtaaggg caaaggtgtc tctgaccatg actttgagga attggtattt 7200 gaagtcgatg tcgtcacagg ctccctgttc ccagagttgg aagtctaccc gtttcttgta 7260 ggcggggttg ggcaaagcga aagtaacatc attgaagaga atcttgccgg ccctgggcat 7320 gaaattgcga gtgatgcgaa aaggctgtgg tacttccgct cggttattga taacctgggc 7380 agctaggacg atctcgtcga aaccgttgat gttgtgtcct acgatgtata attctatgaa 7440 acgcggcgtg cctctgacgt gaggtagctt actgagctca tcaaaggtta ggtctgtggg 7500 gtcagataag gcgtagtgtt cgagagccca ttcgtgcagg tgaggattcg ctttaaggaa 7560 ggaggaccag aggtccactg ccagtgctgt ttgtaactgg tcccggtact gacgaaaatg 7620 ccgtccgact gccatttttt ctggggtgac gcaatagaag gtttgggggt cctgccgcca 7680 gcgatcccac ttgagtttta tggcgaggtc ataggcgatg ttgacgagcc gctggtctcc 7740 agagagtttc atgaccagca tgaaggggat tagctgcttg ccaaaggacc ccatccaggt 7800 gtaggtttcc acatcgtagg tgagaaagag cctttctgtg cgaggatgag agccaatcgg 7860 gaagaactgg atctcctgcc accagttgga ggaatggctg ttgatgtgat ggaagtagaa 7920 ctccctgcga cgcgccgagc attcatgctt gtgcttgtac agacggccgc agtagtcgca 7980 gcgttgcacg ggttgtatct cgtgaatgag ttgtacctgg cttcccttga cgagaaattt 8040 cagtgggaag ccgaggcctg gcgattgtat ctcgtgcttt actatgttgt ctgcatcggc 8100 ctgttcatct tctgtctcga tggtggtcat gctgacgagc cctcgcggga ggcaagtcca 8160 gacctcggcg cggcaggggc ggagctcgag gacgagagcg cgcaggctgg agctgtccag 8220 ggtcctgaga cgctgcggac tcaggttagt aggcagtgtc aggagattaa cttgcatgat 8280 cttttggagg gcgtgcggga ggttcagata gtacttgatc tcaacgggtc cgttggtgga 8340 gatgtcgatg gcttgcaggg ttccgtgtcc cttgggcgct accaccgtgc ccttgttttt 8400 cattttggac ggcggtggct ctgttgcttc ttgcatgttt agaagcggtg tcgagggcgc 8460 gcaccgggcg gcaggggcgg ctcgggaccc ggcggcatgg ctggcagtgg tacgtcggcg 8520 ccgcgcgcgg gtaggttctg gtactgcgcc ctgagaagac tcgcatgcgc gacgacgcgg 8580 cggttgacat cctggatctg acgcctctgg gtgaaagcta ccggccccgt gagcttgaac 8640 ctgaaagaga gttcaacaga atcaatctcg gtatcgttga cggcggcttg cctaaggatt 8700 tcttgcacgt caccagagtt gtcctggtag gcgatctccg ccatgaactg ctcgatctct 8760 tcctcttgaa gatctccgcg gcccgctctc tcgacggtgg ccgcgaggtc gttggagatg 8820 cgcccaatga gttgagagaa tgcattcatg cccgcctcgt tccagacgcg gctgtagacc 8880 acggccccca cgggatctct cgcgcgcatg accacctggg cgaggttgag ctccacgtgg 8940 cgggtgaaga ccgcatagtt gcataggcgc tggaaaaggt agttgagtgt ggtggcgatg 9000 tgctcggtga cgaagaaata catgatccat cgtctcagcg gcatctcgct gacatcgccc 9060 agagcttcca agcgctccat ggcctcgtag aagtccacgg caaaattaaa aaactgggag 9120 tttcgcgcgg acacggtcaa ctcctcttcc agaagacgga taagttcggc gatggtggtg 9180 cgcacctcgc gctcgaaagc ccctgggatt tcttcctcaa tctcttcttc ttccactaac 9240 atctcttcct cttcaggtgg ggctgcagga ggagggggaa cgcggcgacg ccggcggcgc 9300 acgggcagac ggtcgatgaa tctttcaatg acctctccgc ggcggcggcg catggtttca 9360 gtgacggcgc ggccgttctc gcgcggtcgc agagtaaaaa caccgccgcg catctcctta 9420 aagtggtgac tgggaggttc tccgtttggg agggagaggg cgctgattat acattttatt 9480 aattggcccg tagggactgc acgcagagat ctgatcgtgt caagatccac gggatctgaa 9540 aacctttcga cgaaagcgtc taaccagtca cagtcacaag gtaggctgag tacggcttct 9600 tgtgggcggg ggtggttatg tgttcggtct gggtcttctg tttcttcttc atctcgggaa 9660 ggtgagacga tgctgctggt gatgaaatta aagtaggcag ttctaagacg gcggatggtg 9720 gcgaggagca ccaggtcttt gggtccggct tgctggatac gcaggcgatt ggccattccc 9780 caagcattat cctgacatct agcaagatct ttgtagtagt cttgcatgag ccgttctacg 9840 ggcacttctt cctcacccgt tctgccatgc atacgtgtga gtccaaatcc gcgcattggt 9900 tgtaccagtg ccaagtcagc tacgactctt tcggcgagga tggcttgctg tacttgggta 9960 agggtggctt gaaagtcatc aaaatccaca aagcggtggt aagctcctgt attaatggtg 10020 taagcacagt tggccatgac tgaccagtta actgtctggt gaccagggcg cacgagctcg 10080 gtgtatttaa ggcgcgaata ggcgcgggtg tcaaagatgt aatcgttgca ggtgcgcacc 10140 agatactggt accctataag aaaatgcggc ggtggttggc ggtagagagg ccatcgttct 10200 gtagctggag cgccaggggc gaggtcttcc aacataaggc ggtgatagcc gtagatgtac 10260 ctggacatcc aggtgattcc tgcggcggta gtagaagccc gaggaaactc gcgtacgcgg 10320 ttccaaatgt tgcgtagcgg catgaagtag ttcattgtag gcacggtttg accagtgagg 10380 cgcgcgcagt cattgatgct ctatagacac ggagaaaatg aaagcgttca gcgactcgac 10440 tccgtagcct ggaggaacgt gaacgggttg ggtcgcggtg taccccggtt cgagacttgt 10500 actcgagccg gccggagccg cggctaacgt ggtattggca ctcccgtctc gacccagcct 10560 acaaaaatcc aggatacgga atcgagtcgt tttgctggtt tccgaatggc agggaagtga 10620 gtcctatttt ttttttttgc cgctcagatg catcccgtgc tgcgacagat gcgcccccaa 10680 caacagcccc cctcgcagca gcagcagcag caatcacaaa aggctgtccc tgcaactact 10740 gcaactgccg ccgtgagcgg tgcgggacag cccgcctatg atctggactt ggaagagggc 10800 gaaggactgg cacgtctagg tgcgccttca cccgagcggc atccgcgagt tcaactgaaa 10860 aaagattctc gcgaggcgta tgtgccccaa cagaacctat ttagagacag aagcggcgag 10920 gagccggagg agatgcgagc ttcccgcttt aacgcgggtc gtgagctgcg tcacggtttg 10980 gaccgaagac gagtgttgcg ggacgaggat ttcgaagttg atgaaatgac agggatcagt 11040 cctgccaggg cacacgtggc tgcagccaac cttgtatcgg cttacgagca gacagtaaag 11 100 gaagagcgta acttccaaaa gtcttttaat aatcatgtgc gaaccctgat tgcccgcgaa 11160 gaagttaccc ttggtttgat gcatttgtgg gatttgatgg aagctatcat tcagaaccct 11220 actagcaaac ctctgaccgc ccagctgttt ctggtggtgc aacacagcag agacaatgag 11280 gctttcagag aggcgctgct gaacatcacc gaacccgagg ggagatggtt gtatgatctt 11340 atcaacattc tacagagtat catagtgcag gagcggagcc tgggcctggc cgagaaggtg 11400 gctgccatca attactcggt tttgagcttg ggaaaatatt acgctcgcaa aatctacaag 11460 actccatacg ttcccataga caaggaggtg aagatagatg ggttctacat gcgcatgacg 11520 ctcaaggtct tgaccctgag cgatgatctt ggggtgtatc gcaatgacag aatgcatcgc 11580 gcggttagcg ccagcaggag gcgcgagtta agcgacaggg aactgatgca cagtttgcaa 11640 agagctctga ctggagctgg aaccgagggt gagaattact tcgacatggg agctgacttg 11700 cagtggcagc ctagtcgcag ggctctgagc gccgcgacgg caggatgtga gcttccttac 11760 atagaagagg cggatgaagg cgaggaggaa gagggcgagt acttggaaga ctgatggcac 11820 aacccgtgtt ttttgctaga tggaacagca agcaccggat cccgcaatgc gggcggcgct 11880 gcagagccag ccgtccggca ttaactcctc ggacgattgg acccaggcca tgcaacgtat 11940 catggcgttg acgactcgca accccgaagc ctttagacag caaccccagg ccaaccgtct 12000 atcggccatc atggaagctg tagtgccttc ccgctctaat cccactcatg agaaggtcct 12060 ggccatcgtg aacgcgttgg tggagaacaa agctattcgt ccagatgagg ccggactggt 12120 atacaacgct ctcttagaac gcgtggctcg ctacaacagt agcaatgtgc aaaccaattt 12180 ggaccgtatg ataacagatg tacgcgaagc cgtgtctcag cgcgaaaggt tccagcgtga 12240 tgccaacctg ggttcgctgg tggcgttaaa tgctttcttg agtactcagc ctgctaatgt 12300 gccgcgtggt caacaggatt atactaactt tttaagtgct ttgagactga tggtatcaga 12360 agtacctcag agcgaagtgt atcagtccgg tcctgattac ttctttcaga ctagcagaca 12420 gggcttgcag acggtaaatc tgagccaagc ttttaaaaac cttaaaggtt tgtggggagt 12480 gcatgccccg gtaggagaaa gagcaaccgt gtctagcttg ttaactccga actcccgcct 12540 attattactg ttggtagctc ctttcaccga cagcggtagc atcgaccgta attcctattt 12600 gggttaccta ctaaacctgt atcgcgaagc catagggcaa agtcaggtgg acgagcagac 12660 ctatcaagaa attacccaag tcagtcgcgc tttgggacag gaagacactg gcagtttgga 12720 agccactctg aacttcttgc ttaccaatcg gtctcaaaag atccctcctc aatatgctct 12780 tactgcggag gaggagagga tccttagata tgtgcagcag agcgtgggat tgtttctgat 12840 gcaagagggg gcaactccga ctgcagcact ggacatgaca gcgcgaaata tggagcccag 12900 catgtatgcc agtaaccgac ctttcattaa caaactgctg gactacttgc acagagctgc 12960 cgctatgaac tctgattatt tcaccaatgc catcttaaac ccgcactggc tgcccccacc 13020 tggtttctac acgggcgaat atgacatgcc cgaccctaat gacggatttc tgtgggacga 13080 cgtggacagc gatgtttttt cacctctttc tgatcatcgc acgtggaaaa aggaaggcgg 13140 cgatagaatg cattcttctg catcgctgtc cggggtcatg ggtgctaccg cggctgagcc 13200 cgagtctgca agtccttttc ctagtctacc cttttctcta cacagtgtac gtagcagcga 13260 agtgggtaga ataagtcgcc cgagtttaat gggcgaagag gagtatctaa acgattcctt 13320 gctcagaccg gcaagagaaa aaaatttccc aaacaatgga atagaaagtt tggtggataa 13380 aatgagtaga tggaagactt atgctcagga tcacagagac gagcctggga tcatggggat 13440 tacaagtaga gcgagccgta gacgccagcg ccatgacaga cagaggggtc ttgtgtggga 13500 cgatgaggat tcggccgatg atagcagcgt gctggacttg ggtgggagag gaaggggcaa 13560 cccgtttgct catttgcgcc ctcgcttggg tggtatgttg taaaaaaaaa taaaaaaaaa 13620 actcaccaag gccatggcga cgagcgtacg ttcgttcttc tttattatct gtgtctagta 13680 taatgaggcg agtcgtgcta ggcggagcgg tggtgtatcc ggagggtcct cctccttcgt 13740 acgagagcgt gatgcagcag cagcaggcga cggcggtgat gcaatcccca ctggaggctc 13800 cctttgtgcc tccgcgatac ctggcaccta cggagggcag aaacagcatt cgttattcgg 13860 aactggcacc tcagtacgat accaccaggt tgtatctggt ggacaacaag tcggcggaca 13920 ttgcttctct gaactatcag aatgaccaca gcaacttctt gaccacggtg gtgcaaaaca 13980 atgactttac ccctacggaa gccagcaccc agaccattaa ctttgatgaa cgatcgcggt 14040 ggggcggtca gctaaagacc atcatgcata ctaacatgcc aaacgtgaac gagtatatgt 14100 ttagtaacaa gttcaaagcg cgtgtgatgg tgtccagaaa acctcccgac ggtgctgcag 14160 ttggggatac ttatgatcac aagcaggata ttttgaaata tgagtggttc gagtttactt 14220 tgccagaagg caacttttca gttactatga ctattgattt gatgaacaat gccatcatag 14280 ataattactt gaaagtgggt agacagaatg gagtgcttga aagtgacatt ggtgttaagt 14340 tcgacaccag gaacttcaag ctgggatggg atcccgaaac caagttgatc atgcctggag 14400 tgtatacgta tgaagccttc catcctgaca ttgtcttact gcctggctgc ggagtggatt 14460 ttaccgagag tcgtttgagc aaccttcttg gtatcagaaa aaaacagcca tttcaagagg 14520 gttttaagat tttgtatgaa gatttagaag gtggtaatat tccggccctc ttggatgtag 14580 atgcctatga gaacagtaag aaagaacaaa aagccaaaat agaagctgct acagctgctg 14640 cagaagctaa ggcaaacata gttgccagcg actctacaag ggttgctaac gctggagagg 14700 tcagaggaga caattttgcg ccaacacctg ttccgactgc agaatcatta ttggccgatg 14760 tgtctgaagg aacggacgtg aaactcacta ttcaacctgt agaaaaagat agtaagaata 14820 gaagctataa tgtgttggaa gacaaaatca acacagccta tcgcagttgg tatctttcgt 14880 acaattatgg cgatcccgaa aaaggagtgc gttcctggac attgctcacc acctcagatg 14940 tcacctgcgg agcagagcag gtctactggt cgcttccaga catgatgaag gatcctgtca 15000 ctttccgctc cactagacaa gtcagtaact accctgtggt gggtgcagag cttatgcccg 15060 tcttctcaaa gagcttctac aacgaacaag ctgtgtactc ccagcagctc cgccagtcca 15120 cctcgcttac gcacgtcttc aaccgctttc ctgagaacca gattttaatc cgtccgccgg 15180 cgcccaccat taccaccgtc agtgaaaacg ttcctgctct cacagatcac gggaccctgc 15240 cgttgcgcag cagtatccgg ggagtccaac gtgtgaccgt tactgacgcc agacgccgca 15300 cctgtcccta cgtgtacaag gcactgggca tagtcgcacc gcgcgtcctt tcaagccgca 15360 ctttctaaaa aaaaaaaaaa tgtccattct tatctcgccc agtaataaca ccggttgggg 15420 tctgcgcgct ccaagcaaga tgtacggagg cgcacgcaaa cgttctaccc aacatcctgt 15480 ccgtgttcgc ggacattttc gcgctccatg gggcgccctc aagggccgca ctcgcgttcg 15540 aaccaccgtc gatgatgtaa tcgatcaggt ggttgccgac gcccgtaatt atactcctac 15600 tgcgcctaca tctactgtgg atgcagttat tgacagtgta gtggctgacg ctcgcaacta 15660 tgctcgacgt aagagccggc gaaggcgcat tgccagacgc caccgagcta ccactgccat 15720 gcgagccgca agagctctgc tacgaagagc tagacgcgtg gggcgaagag ccatgcttag 15780 ggcggccaga cgtgcagctt cgggcgccag cgccggcagg tcccgcaggc aagcagccgc 15840 tgtcgcagcg gcgactattg ccgacatggc ccaatcgcga agaggcaatg tatactgggt 15900 gcgtgacgct gccaccggtc aacgtgtacc cgtgcgcacc cgtccccctc gcacttagaa 15960 gatactgagc agtctccgat gttgtgtccc agcggcgagg atgtccaagc gcaaatacaa 16020 ggaagaaatg ctgcaggtta tcgcacctga agtctacggc caaccgttga aggatgaaaa 16080 aaaaccccgc aaaatcaagc gggttaaaaa ggacaaaaaa gaagaggaag atggcgatga 16140 tgggctggcg gagtttgtgc gcgagtttgc cccacggcga cgcgtgcaat ggcgtgggcg 16200 caaagttcga catgtgttga gacctggaac ttcggtggtc tttacacccg gcgagcgttc 16260 aagcgctact tttaagcgtt cctatgatga ggtgtacggg gatgatgata ttcttgagca 16320 ggcggctgac cgattaggcg agtttgctta tggcaagcgt agtagaataa cttccaagga 16380 tgagacagtg tcgataccct tggatcatgg aaatcccacc cctagtctta aaccggtcac 16440 tttgcagcaa gtgttacccg taactccgcg aacaggtgtt aaacgcgaag gtgaagattt 16500 gtatcccact atgcaactga tggtacccaa acgccagaag ttggaggacg ttttggagaa 16560 agtaaaagtg gatccagata ttcaacctga ggttaaagtg agacccatta agcaggtagc 16620 gcctggtctg ggggtacaaa ctgtagacat taagattccc actgaaagta tggaagtgca 16680 aactgaaccc gcaaagccta ctgccacctc cactgaagtg caaacggatc catggatgcc 16740 catgcctatt acaactgacg ccgccggtcc cactcgaaga tcccgacgaa agtacggtcc 16800 agcaagtctg ttgatgccca attatgttgt acacccatct attattccta ctcctggtta 16860 ccgaggcact cgctactatc gcagccgaaa cagtacctcc cgccgtcgcc gcaagacacc 16920 tgcaaatcgc agtcgtcgcc gtagacgcac aagcaaaccg actcccggcg ccctggtgcg 16980 gcaagtgtac cgcaatggta gtgcggaacc tttgacactg ccgcgtgcgc gttaccatcc 17040 gagtatcatc acttaatcaa tgttgccgct gcctccttgc agatatggcc ctcacttgtc 17100 gccttcgcgt tcccatcact ggttaccgag gaagaaactc gcgccgtaga agagggatgt 17160 tgggacgcgg aatgcgacgc tacaggcgac ggcgtgctat ccgcaagcaa ttgcggggtg 17220 gttttttacc agccttaatt ccaattatcg ctgctgcaat tggcgcgata ccaggcatag 17280 cttccgtggc ggttcaggcc tcgcaacgac attgacattg gaaaaaaacg tataaataaa 17340 aaaaaaaaaa tacaatggac tctgacactc ctggtcctgt gactatgttt tcttagagat 17400 ggaagacatc aatttttcat ccttggctcc gcgacacggc acgaagccgt acatgggcac 17460 ctggagcgac atcggcacga gccaactgaa cgggggcgcc ttcaattgga gcagtatctg 17520 gagcgggctt aaaaattttg gctcaaccat aaaaacatac gggaacaaag cttggaacag 17580 cagtacagga caggcgctta gaaataaact taaagaccag aacttccaac aaaaagtagt 17640 cgatgggata gcttccggca tcaatggagt ggtagatttg gctaaccagg ctgtgcagaa 17700 aaagataaac agtcgtttgg acccgccgcc agcaacccca ggtgaaatgc aagtggagga 17760 agaaattcct ccgccagaaa aacgaggcga caagcgtccg cgtcccgatt tggaagagac 17820 gctggtgacg cgcgtagatg aaccgccttc ttatgaggaa gcaacgaagc ttggaatgcc 17880 caccactaga ccgatagccc caatggccac cggggtgatg aaaccttctc agttgcatcg 17940 acccgtcacc ttggatttgc cccctccccc tgctgctact gctgtacccg cttctaagcc 18000 tgtcgctgcc ccgaaaccag tcgccgtagc caggtcacgt cccgggggcg ctcctcgtcc 18060 aaatgcgcac tggcaaaata ctctgaacag catcgtgggt ctaggcgtgc aaagtgtaaa 18 120 acgccgtcgc tgcttttaat taaatatgga gtagcgctta acttgcctat ctgtgtatat 18180 gtgtcattac acgccgtcac agcagcagag gaaaaaagga agaggtcgtg cgtcgacgct 18240 gagttacttt caagatggcc accccatcga tgctgcccca atgggcatac atgcacatcg 18300 ccggacagga tgcttcggag tacctgagtc cgggtctggt gcagttcgcc cgcgccacag 18360 acacctactt caatctggga aataagttta gaaatcccac cgtagcgccg acccacgatg 18420 tgaccaccga ccgtagccag cggctcatgt tgcgcttcgt gcccgttgac cgggaggaca 18480 atacatactc ttacaaagtg cggtacaccc tggccgtggg cgacaacaga gtgctggata 18540 tggccagcac gttctttgac attaggggtg tgttggacag aggtcccagt ttcaaaccct 18600 attctggtac ggcttacaac tccctggctc ctaaaggcgc tccaaataca tctcagtgga 18660 ttgcagaagg tgtaaaaaat acaactggtg aggaacacgt aacagaagag gaaaccaata 18720 ctactactta cacttttggc aatgctcctg taaaagctga agctgaaatt acaaaagaag 18780 gactcccagt aggtttggaa gtttcagatg aagaaagtaa accgatttat gctgataaaa 18840 catatcagcc agaacctcag ctgggagatg aaacttggac tgaccttgat ggaaaaaccg 18900 aaaagtatgg aggcagggct ctcaaacccg atactaagat gaaaccatgc tacgggtcct 18960 ttgccaaacc tactaatgtg aaaggcggtc aggcaaaaca aaaaacaacg gagcagccaa 19020 atcagaaagt cgaatatgat atcgacatgg agttttttga tgcggcatcg cagaaaacaa 19080 acttaagtcc taaaattgtc atgtatgcag aaaatgtaaa tttggaaact ccagacactc 19140 atgtagtgta caaacctgga acagaagaca caagttccga agctaatttg ggacaacaat 19200 ctatgcccaa cagacccaac tacattggct tcagagataa ctttattgga cttatgtact 19260 ataacagtac tggtaacatg ggggtgctgg ctggtcaagc gtctcagtta aatgcagtgg 19320 ttgacttgca ggacagaaac acagaacttt cttaccaact cttgcttgac tctctgggcg 19380 acagaaccag atactttagc atgtggaatc aggctgtgga cagttatgat cctgatgtac 19440 gtgttattga aaatcatggt gtggaagatg aacttcccaa ctactgtttt ccactggacg 19500 gcataggtgt tccaacaacc agttacaaat caatagttcc aaatggagac aatgcgccta 19560 attggaagga acctgaagta aatggaacaa gtgagatcgg acagggtaat ttgtttgcca 19620 tggaaattaa ccttcaagcc aatctatggc gaagtttcct ttattccaat gtggctctat 19680 atctcccaga ctcgtacaaa tacaccccgt ccaatgtcac tcttccagaa aacaaaaaca 19740 cctacgacta catgaacggg cgggtggtgc cgccatctct agtagacacc tatgtgaaca 19800 ttggtgccag gtggtctctg gatgccatgg acaatgtcaa cccattcaac caccaccgta 19860 acgctggctt gcgttaccga tccatgcttc tgggtaacgg acgttatgtg cctttccaca 19920 tacaagtgcc tcaaaaattc ttcgctgtta aaaacctgct gcttctccca ggctcctaca 19980 cttatgagtg gaactttagg aaggatgtga acatggttct acagagttcc ctcggtaacg 20040 acctgcgggt agatggcgcc agcatcagtt tcacgagcat caacctctat gctacttttt 20100 tccccatggc tcacaacacc gcttccaccc ttgaagccat gctgcggaat gacaccaatg 20160 atcagtcatt caacgactac ctatctgcag ctaacatgct ctaccccatt cctgccaatg 20220 caaccaatat tcccatttcc attccttctc gcaactgggc ggctttcaga ggctggtcat 20280 ttaccagact gaaaaccaaa gaaactccct ctttggggtc tggatttgac ccctactttg 20340 tctattctgg ttctattccc tacctggatg gtaccttcta cctgaaccac acttttaaga 20400 aggtttccat catgtttgac tcttcagtga gctggcctgg aaatgacagg ttactatctc 20460 ctaacgaatt tgaaataaag cgcactgtgg atggcgaagg ctacaacgta gcccaatgca 20520 acatgaccaa agactggttc ttggtacaga tgctcgccaa ctacaacatc ggctatcagg 20580 gcttctacat tccagaagga tacaaagatc gcatgtattc atttttcaga aacttccagc 20640 ccatgagcag gcaggtggtt gatgaggtca attacaaaga cttcaaggcc gtcgccatac 20700 cctaccaaca caacaactct ggctttgtgg gttacatggc tccgaccatg cgccaaggtc 20760 aaccctatcc cgctaactat ccctatccac tcattggaac aactgccgta aatagtgtta 20820 cgcagaaaaa gttcttgtgt gacagaacca tgtggcgcat accgttctcg agcaacttca 20880 tgtctatggg ggcccttaca gacttgggac agaatatgct ctatgccaac tcagctcatg 20940 ctctggacat gacctttgag gtggatccca tggatgagcc caccctgctt tatcttctct 21000 tcgaagtttt cgacgtggtc agagtgcatc agccacaccg cggcatcatc gaggcagtct 21060 acctgcgtac accgttctcg gccggtaacg ctaccacgta agaagcttct tgcttcttgc 21120 aaatagcagc tgcaaccatg gcctgcggat cccaaaacgg ctccagcgag caagagctca 21180 gagccattgt ccaagacctg ggttgcggac cctatttttt gggaacctac gataagcgct 21240 tcccggggtt catggccccc gataagctcg cctgtgccat tgtaaatacg gccggacgtg 21300 agacgggggg agagcactgg ttggctttcg gttggaaccc acgttctaac acctgctacc 21360 tttttgatcc ttttggattc tcggatgatc gtctcaaaca gatttaccag tttgaatatg 21420 agggtctcct gcgccgcagc gctcttgcta ccaaggaccg ctgtattacg ctggaaaaat 21480 ctacccagac cgtgcagggt ccccgttctg ccgcctgcgg acttttctgc tgcatgttcc 21540 ttcacgcctt tgtgcactgg cctgaccgtc ccatggacgg aaaccccacc atgaaattgc 21600 taactggagt gccaaacaac atgcttcatt ctcctaaagt ccagcccacc ctgtgtgaca 21660 atcaaaaagc actctaccat tttcttaata cccattcgcc ttattttcgc tcccatcgta 21720 cacacatcga aagggccact gcgttcgacc gtatggatgt tcaataatga ctcatgtaaa 21780 caacgtgttc aataaacatc actttatttt tttacatgta tcaaggctct gcattactta 21840 tttatttaca agtcgaatgg gttctgacga gaatcagaat gacccgcagg cagtgatacg 21900 ttgcggaact gatacttggg ttgccacttg aattcgggaa tcaccaactt gggaaccggt 21960 atatcgggca ggatgtcact ccacagcttt ctggtcagct gcaaagctcc aagcaggtca 22020 ggagccgaaa tcttgaaatc acaattagga ccagtgcttt gagcgcgaga gttgcggtac 22080 accggattgc agcactgaaa caccatcagc gacggatgtc tcacgcttgc cagcacggtg 22140 ggatctgcaa tcatgcccac atccagatct tcagcattgg caatgctgaa cggggtcatc 22200 ttgcaggtct gcctacccat ggcgggcacc caattaggct tgtggttgca atcgcagtgc 22260 agggggatca gtatcatctt ggcctgatcc tgtctgattc ctggatacac ggctctcatg 22320 aaagcatcat attgcttgaa agcctgctgg gctttactac cctcggtata aaacatcccg 22380 caggacctgc tcgaaaactg gttagctgca cagccggcat cattcacaca gcagcgggcg 22440 tcattgttag ctatttgcac cacacttctg ccccagcggt tttgggtgat tttggttcgc 22500 tcgggattct cctttaaggc tcgttgtccg ttctcgctgg ccacatccat ctcgataatc 22560 tgctccttct gaatcataat attgccatgc aggcacttca gcttgccctc ataatcattg 22620 cagccatgag gccacaacgc acagcctgta cattcccaat tatggtgggc gatctgagaa 22680 aaagaatgta tcattccctg cagaaatctt cccatcatcg tgctcagtgt cttgtgacta 22740 gtgaaagtta actggatgcc tcggtgctcc tcgtttacgt actggtgaca gatgcgcttg 22800 tattgttcgt gttgctcagg cattagttta aaagaggttc taagttcgtt atccagcctg 22860 tacttctcca tcagcagaca catcacttcc atgcctttct cccaagcaga caccaggggc 22920 aagctaatcg gattcttaac agtgcaggca gcagctcctt tagccagagg gtcatcttta 22980 gcgatcttct caatgcttct tttgccatcc ttctcaacga tgcgcacggg cgggtagctg 23040 aaacccactg ctacaagttg cgcctcttct ctttcttctt cgctgtcttg actgatgtct 23100 tgcatgggga tatgtttggt cttccttggc ttctttttgg ggggtatcgg aggaggagga 23160 ctgtcgctcc gttccggaga cagggaggat tgtgacgttt cgctcaccat taccaactga 23220 ctgtcggtag aagaacctga ccccacacgg cgacaggtgt ttctcttcgg gggcagaggt 23280 ggaggcgatt gcgaagggct gcggtccgac ctggaaggcg gatgactggc agaacccctt 23340 ccgcgttcgg gggtgtgctc cctgtggcgg tcgcttaact gatttccttc gcggctggcc 23400 attgtgttct cctaggcaga gaaacaacag acatggaaac tcagccattg ctgtcaacat 23460 cgccacgagt gccatcacat ctcgtcctca gcgacgagga aaaggagcag agcttaagca 23520 ttccaccgcc cagtcctgcc accacctcta ccctagaaga taaggaggtc gacgcatctc 23580 atgacatgca gaataaaaaa gcgaaagagt ctgagacaga catcgagcaa gacccgggct 23640 atgtgacacc ggtggaacac gaggaagagt tgaaacgctt tctagagaga gaggatgaaa 23700 actgcccaaa acaacgagca gataactatc accaagatgc tggaaatagg gatcagaaca 23760 ccgactacct catagggctt gacggggaag acgcgctcct taaacatcta gcaagacagt 23820 cgctcatagt caaggatgca ttattggaca gaactgaagt gcccatcagt gtggaagagc 23880 tcagccgcgc ctacgagctt aacctctttt cacctcgtac tccccccaaa cgtcagccaa 23940 acggcacctg cgagccaaat cctcgcttaa acttttatcc agcttttgct gtgccagaag 24000 tactggctac ctatcacatc ttttttaaaa atcaaaaaat tccagtctcc tgccgcgcta 24060 atcgcacccg cgccgatgcc ctactcaatc tgggacctgg ttcacgctta cctgatatag 24120 cttccttgga agaggttcca aagatcttcg agggtctggg caataatgag actcgggccg 24180 caaatgctct gcaaaaggga gaaaatggca tggatgagca tcacagcgtt ctggtggaat 24 240 tggaaggcga taatgccaga ctcgcagtac tcaagcgaag catcgaggtc acacacttcg 24300 catatcccgc tgtcaacctg ccccctaaag tcatgacggc ggtcatggac cagttactca 24360 ttaagcgcgc aagtcccctt tcagaagaca tgcatgaccc agatgcctgt gatgagggta 24420 aaccagtggt cagtgatgag cagctaaccc gatggctggg caccgactct cccagggatt 24480 tggaagagcg tcgcaagctt atgatggccg tggtgctggt taccgtagaa ctagagtgtc 24540 tccgacgttt ctttaccgat tcagaaacct tgcgcaaact cgaagagaat ctgcactaca 24600 cttttagaca cggctttgtg cggcaggcat gcaagatatc taacgtggaa ctcaccaacc 24660 tggtttccta catgggtatt ctgcatgaga atcgcctagg acaaagcgtg ctgcacagca 24720 ccctgaaggg ggaagcccgc cgtgattaca tccgcgattg tgtctatctg tacctgtgcc 24780 acacgtggca aaccggcatg ggtgtatggc agcaatgttt agaagaacag aacttgaaag 24840 agcttgacaa gctcttacag aaatctctta aggttctgtg gacagggttc gacgagcgca 24900 ccgtcgcttc cgacctggca gacctcatct tcccagagcg tctcagggtt actttgcgaa 24960 acggattgcc tgactttatg agccagagca tgcttaacaa ttttcgctct ttcatcctgg 25020 aacgctccgg tatcctgccc gccacctgct gcgcactgcc ctccgacttt gtgcctctca 25080 cctaccgcga gtgccccccg ccgctatgga gtcactgcta cctgttccgt ctggccaact 25 140 atctctccta ccactcggat gtgatcgagg atgtgagcgg agacggcttg ctggagtgtc 25200 actgccgctg caatctgtgc acgccccacc ggtccctagc ttgcaacccc cagttgatga 25260 gcgaaaccca gataataggc acctttgaat tgcaaggccc cagcagccaa ggcgatgggt 25320 cttctcctgg gcaaagttta aaactgaccc cgggactgtg gacctccgcc tacttgcgca 25380 agtttgctcc ggaagattac cacccctatg aaatcaagtt ctatgaggac caatcacagc 25440 ctccaaaggc cgaactttcg gcctgcgtca tcacccaggg ggcaattctg gcccaattgc 25500 aagccatcca aaaatcccgc caagaatttc tactgaaaaa gggtaagggg gtctaccttg 25560 acccccagac cggcgaggaa ctcaacacaa ggttccctca ggatgtccca acgacgagaa 25620 aacaagaagt tgaaggtgca gccgccgccc ccagaagata tggaggaaga ttgggacagt 25680 caggcagagg aggcggagga ggacagtctg gaggacagtc tggaggaaga cagtttggag 25740 gaggaaaacg aggaggcaga ggaggtggaa gaagtaaccg ccgacaaaca gttatcctcg 25800 gctgcggaga caagcaacag cgctaccatc tccgctccga gtcgaggaac ccggcggcgt 25860 cccagcagta gatgggacga gaccggacgc ttcccgaacc caaccagcgc ttccaagacc 25920 ggtaagaagg atcggcaggg atacaagtcc tggcgggggc ataagaatgc catcatctcc 25980 tgcttgcatg agtgcggggg caacatatcc ttcacgcggc gctacttgct attccaccat 26040 ggggtgaact ttccgcgcaa tgttttgcat tactaccgtc acctccacag cccctactat 26100 agccagcaaa tcccggcagt ctcgacagat aaagacagcg gcggcgacct ccaacagaaa 26160 accagcagcg gcagttagaa aatacacaac aagtgcagca acaggaggat taaagattac 26220 agccaacgag ccagcgcaaa cccgagagtt aagaaatcgg atctttccaa ccctgtatgc 26280 catcttccag cagagtcggg gtcaagagca ggaactgaaa ataaaaaacc gatctctgcg 26340 ttcgctcacc agaagttgtt tgtatcacaa gagcgaagat caacttcagc gcactctcga 26400 ggacgccgag gctctcttca acaagtactg cgcgctgact cttaaagagt aggcagcgac 26460 cgcgcttatt caaaaaaggc gggaattaca tcatcctcga catgagtaaa gaaattccca 26520 cgccttacat gtggagttat caaccccaaa tgggattggc ggcaggcgcc tcccaggact 26580 actccacccg catgaattgg ctcagcgccg ggccttctat gatttctcga gttaatgata 26640 tacgcgccta ccgaaaccaa atacttttgg aacagtcagc tcttaccacc acgccccgcc 26700 aacaccttaa tcccagaaat tggcccgccg ccctagtgta ccaggaaagt cccgctccca 26760 ccactgtatt acttcctcga gacgcccagg ccgaagtcca aatgactaat gcaggtgcgc 26820 agttagctgg cggctccacc ctatgtcgtc acaggcctcg gcataatata aaacgcctga 26880 tgatcagagg ccgaggtatc cagctcaacg acgagtcggt gagctctccg cttggtctac 26940 gaccagacgg aatctttcag attgccggct gcgggagatc ttccttcacc cctcgtcagg 27000 ctgttctgac tttggaaagt tcgtcttcgc aaccccgctc gggcggaatc gggaccgttc 27060 aatttgtgga ggagtttact ccctctgtct acttcaaccc cttctccgga tctcctgggc 27120 attacccgga cgagttcata ccgaacttcg acgcgattag cgagtcagtg gacggctacg 27180 attgatgtct ggtgacgcgg ctgagctatc tcggctgcga catctagacc actgccgccg 27240 ctttcgctgc tttgcccggg aactcattga gttcatctac ttcgaactcc ccaaggatca 27300 ccctcaaggt ccggcccacg gagtgcggat ttctatcgaa ggcaaaatag actctcgcct 27360 gcaacgaatt ttctcccagc ggcccgtgct gatcgagcga gaccagggaa acaccacggt 27420 ttccatctac tgcatttgta atcaccccgg attgcatgaa agcctttgct gtcttatgtg 27480 tactgagttt aataaaaact gaattaagac tctcctacgg actgccgctt cttcaacccg 27540 gattttacaa ccagaagaac gaaacttttc ctgtcgtcca ggactctgtt aacttcacct 27600 ttcctactca caaactagaa gctcaacgac tacaccgctt ttccagaagc attttcccta 27660 ctaatactac tttcaaaacc ggaggtgagc tccaaggtct tcctacagaa aacccttggg 27720 tggaagcggg ccttgtagtg ctaggaattc ttgcgggtgg gcttgtgatt attctttgct 27780 acctatacac accttgcttc actttcttag tggtgttgtg gtattggttt aaaaaatggg 27840 gcccatacta gtcttgcttg ttttactttc gcttttggaa ccgggttctg ccaattacga 27900 tccatgtcta gacttcgacc cagaaaactg cacacttact tttgcacccg acacaagccg 27960 catctgtgga gttcatcgcc tctcttacga acttggcccc caacgacaaa aatttacctg 28020 catggtggga atcaacccca tagttatcac ccagcaaagt ggagatacta agggttgcat 28080 tcactgctcc tgcgattcca tcgagtgcac ctacaccctg ctgaagaccc tatgcggcct 28140 aagagacctg ctaccaatga attaaaaaat gattaataaa aaatcactta cttgaaatca 28200 gcaataaggt ctctgttgaa attttctccc agcagcacct cacttccctc ttcccaactc 28260 tggtattcta aaccccgttc agcggcatac tttctccata ctttaaaggg gatgtcaaat 28320 tttagctcct ctcctgtacc cacaatcttc atgtctttct tcccagatga ccaagagagt 28380 ccggctcagt gactccttca accctgtcta cccctatgaa gatgaaagca cctcccaaca 28440 cccctttata aacccagggt ttatttcccc aaatggcttc acacaaagcc caaacggagt 28500 tcttacttta aaatgtttaa ccccactaac aaccacaggc ggatctctac agctaaaagt 28560 gggaggggga cttacagtgg atgacaccaa cggttttttg aaagaaaaca taagtgccac 28620 cacaccactc gttaagactg gtcactctat aggtttacca ctaggagccg gattgggaac 28680 gaatgaaaat aaactttgta tcaaattagg acaaggactt acattcaatt caaacaacat 28740 ttgcattgat gacaatatta acaccttatg gacaggagtc aaccccaccg aagccaactg 28800 tcaaatcatg aactccagtg aatctaatga ttgcaaatta attctaacac tagttaaaac 28860 tggagcacta gtcactgcat ttgtttatgt tataggagta tctaacaatt ttaatatgct 28920 aactacacac agaaatataa attttactgc agagctgttt ttcgattcta ctggtaattt 28980 actaactaga ctctcatccc tcaaaactcc acttaatcat aaatcaggac aaaacatggc 29040 tactggtgcc attactaatg ctaaaggttt catgcccagc acgactgcct atcctttcaa 29100 tgataattct agagaaaaag aaaactacat ttacggaact tgttactaca cagctagtga 29160 tcgcactgct tttcccattg acatatctgt catgcttaac cgaagagcaa taaatgacga 29220 gacatcatat tgtattcgta taacttggtc ctggaacaca ggagatgccc cagaggtgca 29280 aacctctgct acaaccctag tcacctcccc atttaccttt tactacatca gagaagacga 29340 ctgacaaata aagtttgcga tcgccaggcc accatgacag tgctggcgcc agcctggagc 29400 ccaacaacct atctcctcct gctgctgctg ctgagctcgg gactcagtgg gacccaggac 29460 tgctccttcc aacacagccc catctcctcc gacttcgctg tcaaaatccg tgagctgtct 29520 gactacctgc ttcaagatta cccagtcacc gtggcctcca acctccagga cgaggagctc 29580 tgcgggggcc tctggcggct ggtcctggca cagcgctgga tggagcggct caagactgtc 29640 gctgggtcca agatgcaagg cttgctggag cgcgtgaaca cggagataca ctttgtcacc 29700 aaatgtgcct ttcagccccc ccccagctgt cttcgcttcg tccagaccaa catctcccgc 29760 ctcctacagg agacctccga gcagctggtg gcgctgaagc cctggatcac tcgccagaac 29820 ttctcccggt gcctggagct gcagtgtcag cccgactcct caaccctgcc acccccatgg 29880 agtccccggc ccctggaggc cacagccccg ggaagcggag ctactaactt cagcctgctg 29940 aagcaggctg gagacgtgga ggagaaccct ggacctcagg tctccactgc tgcccttgcc 30000 gtcctcctct gcaccatggc tctctgcaac caggtcctct ctgcaccact tgctgctgac 30060 acgccgaccg cctgctgctt cagctacacc tcccgacaga ttccacagaa tttcatagct 30120 gactactttg agacgagcag ccagtgctcc aagcccagtg tcatcttcct aaccaagaga 30180 ggccggcagg tctgtgctga ccccagtgag gagtgggtcc agaaatacgt cagtgacctg 30240 gagctgagtg ccggaagcgg agagggcaga ggaagtctgc taacatgcgg tgacgtcgag 30300 gagaatcctg gacctgcctt gacctttgct ttactggtgg ccctcctggt gctcagctgc 30360 aagtcaagct gctctgtggg ctgtgatctg cctcaaaccc acagcctggg tagcaggagg 30420 accttgatgc tcctggcaca gatgaggaga atctctcttt tctcctgctt gaaggacaga 30480 catgactttg gatttcccca ggaggagttt ggcaaccagt tccaaaaggc tgaaaccatc 30540 cctgtcctcc atgagatgat ccagcagatc ttcaatctct tcagcacaaa ggactcatct 30600 gctgcttggg atgagaccct cctagacaaa ttctacactg aactctacca gcagctgaat 30660 gacctggaag cctgtgtgat acagggggtg ggggtgacag agactcccct gatgaaggag 30720 gactccattc tggctgtgag gaaatacttc caaagaatca ctctctatct gaaagagaag 30780 aaatacagcc cttgtgcctg ggaggttgtc agagcagaaa tcatgagatc tttttctttg 30840 tcaacaaact tgcaagaaag tttaagaagt aaggaataag ctagcttgac tgactgagat 30900 acagcgtacc ttcagctcac agacatgata agatacattg atgagtttgg acaaaccaca 30960 actagaatgc agtgaaaaaa atgctttatt tgtgaaattt gtgatgctat tgctttattt 31020 gtaaccatta taagctgcaa taaacaagtt aacaacaaca attgcattca ttttatgttt 31080 caggttcagg gggaggtgtg ggaggttttt taaagcaagt aaaacctcta caaatgtggt 31140 agtcgtcagc tatcctgcag gaacttgttt atttgaaaat caattcacaa aatccgagta 31200 gttattttgc ctcccccttc ccatttaaca gaatacacca atctctcccc acgcacagct 31260 ttaaacattt ggataccatt agatatagac atggttttag attccacatt ccaaacagtt 31320 tcagagcgag ccaatctggg gtcagtgata gataaaaatc catcgggata gtcttttaaa 31380 gcgctttcac agtccaactg ctgcggatgc gactccggag tctggatcac ggtcatctgg 31440 aagaagaacg atgggaatca taatccgaaa acggtatcgg acgattgtgt ctcatcaaac 31500 ccacaagcag ccgctgtctg cgtcgctccg tgcgactgct gtttatggga tcagggtcca 31560 cagtgtcctg aagcatgatt ttaatagccc ttaacatcaa ctttctggtg cgatgcgcgc 31620 agcaacgcat tctgatttca ctcaaatctt tgcagtaggt acaacacatt attacaatat 31680 tgtttaataa accataatta aaagcgctcc agccaaaact catatctgat ataatcgccc 31740 ctgcatgacc atcataccaa agtttaatat aaattaaatg acgttccctc aaaaacacac 31800 tacccacata catgatctct tttggcatgt gcatattaac aatctgtctg taccatggac 31860 aacgttggtt aatcatgcaa cccaatataa ccttccggaa ccacactgcc aacaccgctc 31920 ccccagccat gcattgaagt gaaccctgct gattacaatg acaatgaaga acccaattct 31980 ctcgaccgtg aatcacttga gaatgaaaaa tatctatagt ggcacaacat agacataaat 32040 gcatgcatct tctcataatt tttaactcct caggatttag aaacatatcc cagggaatag 32100 gaagctcttg cagaacagta aagctggcag aacaaggaag accacgaaca caacttacac 32160 tatgcatagt catagtatca caatctggca acagcgggtg gtcttcagtc atagaagctc 32220 gggtttcatt ttcctcacaa cgtggtaact gggctctggt gtaagggtga tgtctggcgc 32280 atgatgtcga gcgtgcgcgc aaccttgtca taatggagtt gcttcctgac attctcgtat 32340 tttgtatagc aaaacgcggc cctggcagaa cacactcttc ttcgccttct atcctgccgc 32400 ttagcgtgtt ccgtgtgata gttcaagtac aaccacactc ttaagttggt caaaagaatg 32460 ctggcttcag ttgtaatcaa aactccatcg catctaatcg ttctgaggaa atcatccaag 32520 caatgcaact ggattgtgtt tcaagcagga gaggagaggg aagagacgga agaaccatgt 32580 taatttttat tccaaacgat ctcgcagtac ttcaaattgt agatcgcgca gatggcatct 32640 ctcgccccca ctgtgttggt gaaaaagcac agctagatca aaagaaatgc gattttcaag 32700 gtgctcaacg gtggcttcca gcaaagcctc cacgcgcaca tccaagaaca aaagaatacc 32760 aaaagaagga gcattttcta actcctcaat catcatatta cattcctgca ccattcccag 32820 ataattttca gctttccagc cttgaattat tcgtgtcagt tcttgtggta aatccaatcc 32880 acacattaca aacaggtccc ggagggcgcc ctccaccacc attcttaaac acaccctcat 32940 aatgacaaaa tatcttgctc ctgtgtcacc tgtagcgaat tgagaatggc aacatcaatt 33000 gacatgccct tggctctaag ttcttcttta agttctagtt gtaaaaactc tctcatatta 33060 tcaccaaact gcttagccag aagccccccg ggaacaagag caggggacgc tacagtgcag 33 120 tacaagcgca gacctcccca attggctcca gcaaaaacaa gattggaata agcatattgg 33180 gaaccgccag taatatcatc gaagttgctg gaaatataat caggcagagt ttcttgtaaa 33 240 aattgaataa aagaaaaatt tgccaaaaaa acattcaaaa cctctgggat gcaaatgcaa 33 300 taggttaccg cgctgcgctc caacattgtt agttttgaat tagtctgcaa aaataaaaaa 33360 aaaaacaagc gtcatatcat agtagcctga cgaacagatg gataaatcag tctttccatc 33420 acaagacaag ccacagggtc tccagctcga ccctcgtaaa acctgtcatc atgattaaac 33480 aacagcaccg aaagttcctc gcggtgacca gcatgaataa ttcttgatga agcatacaat 33540 ccagacatgt tagcatcagt taacgagaaa aaacagccaa catagccttt gggtataatt 33600 atgcttaatc gtaagtatag caaagccacc cctcgcggat acaaagtaaa aggcacagga 33660 gaataaaaaa tataattatt tctctgctgc tgttcaggca acgtcgcccc cggtccctct 33720 aaatacacat acaaagcctc atcagccatg gcttaccaga caaagtacag cgggcacaca 33780 aagcacaagc tctaaagtga ctctccaacc tctccacaat atatatatac acaagcccta 33840 aactgacgta atgggagtaa agtgtaaaaa atcccgccaa acccaacaca caccccgaaa 33900 ctgcgtcacc agggaaaagt acagtttcac ttccgcaatc ccaacaggcg taacttcctc 33960 tttctcacgg tacgtgatat cccactaact tgcaacgtca ttttcccacg gtcgcaccgc 34020 cccttttagc cgttaacccc acagccaatc accacacgat ccacactttt taaaatcacc 34080 tcatttacat attggcacca ttccatctat aaggtatatt atatagatag a 34131 <210> 19 <211> 34432 <212> DNA <213> Artificial Sequence <220> <223> NG-346 virus genome sequence comprising a transgene cassette that encodes Flt3 Ligand, MIP1a and CD80, employing SSA and P2A sequence, inserted in the region BY <400> 19 tctatctata taatatacct tatagatgga atggtgccaa tatgtaaatg aggtgatttt 60 aaaaagtgtg gatcgtgtgg tgattggctg tggggttaac ggctaaaagg ggcggtgcga 120 ccgtgggaaa atgacgtttt gtgggggtgg agtttttttg caagttgtcg cgggaaatgt 180 gacgcataaa aaggcttttt tctcacggaa ctacttagtt ttcccacggt atttaacagg 240 aaatgaggta gttttgaccg gatgcaagtg aaaattgttg attttcgcgc gaaaactgaa 300 tgaggaagtg tttttctgaa taatgtggta tttatggcag ggtggagtat ttgttcaggg 360 ccaggtagac tttgacccat tacgtggagg tttcgattac cgtgtttttt acctgaattt 420 ccgcgtaccg tgtcaaagtc ttctgttttt acgtaggtgt cagctgatcg ctagggtatt 480 tatacctcag ggtttgtgtc aagaggccac tcttgagtgc cagcgagaag agttttctcc 540 tctgcgccgg cagtttaata ataaaaaaat gagagatttg cgatttctgc ctcaggaaat 600 aatctctgct gagactggaa atgaaatatt ggagcttgtg gtgcacgccc tgatgggaga 660 cgatccggag ccacctgtgc agctttttga gcctcctacg cttcaggaac tgtatgattt 720 agaggtagag ggatcggagg attctaatga ggaagctgta aatggctttt ttaccgattc 780 tatgctttta gctgctaatg aagggttaga attagatccg cctttggaca cttttgatac 840 tccaggggta attgtggaaa gcggtacagg tgtaagaaaa ttacctgatt tgagttccgt 900 ggactgtgat ttgcactgct atgaagacgg gtttcctccg agtgatgagg aggaccatga 960 aaaggagcag tccatgcaga ctgcagcggg tgagggagtg aaggctgcca atgttggttt 1020 tcagttggat tgcccggagc ttcctggaca tggctgtaag tcttgtgaat ttcacaggaa 1080 aaatactgga gtaaaggaac tgttatgttc gctttgttat atgagaacgc actgccactt 1140 tatttacagt aagtgtgttt aagttaaaat ttaaaggaat atgctgtttt tcacatgtat 1200 attgagtgtg agttttgtgc ttcttattat aggtcctgtg tctgatgctg atgaatcacc 1260 atctcctgat tctactacct cacctcctga gattcaagca cctgttcctg tggacgtgcg 1320 caagcccatt cctgtgaagc ttaagcctgg gaaacgtcca gcagtggaaa aacttgagga 1380 cttgttacag ggtggggacg gacctttgga cttgagtaca cggaaacgtc caagacaata 1440 agtgttccat atccgtgttt acttaaggtg acgtcaatat ttgtgtgaca gtgcaatgta 1500 ataaaaatat gttaactgtt cactggtttt tattgctttt tgggcgggga ctcaggtata 1560 taagtagaag cagacctgtg tggttagctc ataggagctg gctttcatcc atggaggttt 1620 gggccatttt ggaagacctt aggaagacta ggcaactgtt agagaacgct tcggacggag 1680 tctccggttt ttggagattc tggttcgcta gtgaattagc tagggtagtt tttaggataa 1740 aacaggacta taaacaagaa tttgaaaagt tgttggtaga ttgcccagga ctttttgaag 1800 ctcttaattt gggccatcag gttcacttta aagaaaaagt tttatcagtt ttagactttt 1860 caaccccagg tagaactgct gctgctgtgg cttttcttac ttttatatta gataaatgga 1920 tcccgcagac tcatttcagc aggggatacg ttttggattt catagccaca gcattgtgga 1980 gaacatggaa ggttcgcaag atgaggacaa tcttaggtta ctggccagtg cagcctttgg 2040 gtgtagcggg aatcctgagg catccaccgg tcatgccagc ggttctggag gaggaacagc 2100 aagaggacaa cccgagagcc ggcctggacc ctccagtgga ggaggcggag tagctgactt 2160 gtctcctgaa ctgcaacggg tgcttactgg atctacgtcc actggacggg ataggggcgt 2220 taagagggag agggcatcta gtggtactga tgctagatct gagttggctt taagtttaat 2280 gagtcgcaga cgtcctgaaa ccatttggtg gcatgaggtt cagaaagagg gaagggatga 2340 agtttctgta ttgcaggaga aatattcact ggaacaggtg aaaacatgtt ggttggagcc 2400 tgaggatgat tgggaggtgg ccattaaaaa ttatgccaag atagctttga ggcctgataa 2460 acagtataag attactagac ggattaatat ccggaatgct tgttacatat ctggaaatgg 2520 ggctgaggtg gtaatagata ctcaagacaa ggcagttatt agatgctgca tgatggatat 2580 gtggcctggg gtagtcggta tggaagcagt aacttttgta aatgttaagt ttaggggaga 2640 tggttataat ggaatagtgt ttatggccaa taccaaactt atattgcatg gttgtagctt 2700 ttttggtttc aacaatacct gtgtagatgc ctggggacag gttagtgtac ggggatgtag 2760 tttctatgcg tgttggattg ccacagctgg cagaaccaag agtcaattgt ctctgaagaa 2820 atgcatattt caaagatgta acctgggcat tctgaatgaa ggcgaagcaa gggtccgcca 2880 ctgcgcttct acagatactg gatgttttat tttgattaag ggaaatgcca gcgtaaagca 2940 taacatgatt tgcggtgctt ccgatgagag gccttatcaa atgctcactt gtgctggtgg 3000 gcattgtaat atgctggcta ctgtgcatat tgtttcccat caacgcaaaa aatggcctgt 3060 ttttgatcac aatgtgatga cgaagtgtac catgcatgca ggtgggcgta gaggaatgtt 3120 tatgccttac cagtgtaaca tgaatcatgt gaaagtgttg ttggaaccag atgccttttc 3180 cagaatgagc ctaacaggaa tttttgacat gaacatgcaa atctggaaga tcctgaggta 3240 tgatgatacg agatcgaggg tacgcgcatg cgaatgcgga ggcaagcatg ccaggttcca 3300 gccggtgtgt gtagatgtga ctgaagatct cagaccggat catttggtta ttgcccgcac 3360 tggagcagag ttcggatcca gtggagaaga aactgactaa ggtgagtatt gggaaaactt 3420 tggggtggga ttttcagatg gacagattga gtaaaaattt gttttttctg tcttgcagct 3480 gtcatgagtg gaaacgcttc ttttaagggg ggagtcttca gcccttatct gacagggcgt 3540 ctcccatcct gggcaggagt tcgtcagaat gttatgggat ctactgtgga tggaagaccc 3600 gtccaacccg ccaattcttc aacgctgacc tatgctactt taagttcttc acctttggac 3660 gcagctgcag ctgccgccgc cgcttctgtt gccgctaaca ctgtgcttgg aatgggttac 3720 tatggaagca tcatggctaa ttccacttcc tctaataacc cttctaccct gactcaggac 3780 aagttacttg tccttttggc ccagctggag gctttgaccc aacgtctggg tgaactttct 3840 cagcaggtgg tcgagttgcg agtacaaact gagtctgctg tcggcacggc aaagtctaaa 3900 taaaaaaatc ccagaatcaa tgaataaata aacaagcttg ttgttgattt aaaatcaagt 3960 gtttttattt catttttcgc gcacggtatg ccctagacca ccgatctcta tcattgagaa 4020 ctcggtggat tttttccagg atcctataga ggtgggattg aatgtttaga tacatgggca 4080 ttaggccgtc tttggggtgg agatagctcc attgaaggga ttcatgctcc ggggtagtgt 4140 tgtaaatcac ccagtcataa caaggtcgca gtgcatggtg ttgcacaata tcttttagaa 4200 gtaggctgat tgccacagat aagcccttgg tgtaggtgtt tacaaaccgg ttgagctggg 4260 atgggtgcat tcggggtgaa attatgtgca ttttggattg gatttttaag ttggcaatat 4320 tgccgccaag atcccgtctt gggttcatgt tatgaaggac caccaagacg gtgtatccgg 4380 tacatttagg aaatttatcg tgcagcttgg atggaaaagc gtggaaaaat ttggagacac 4440 ccttgtgtcc tccaagattt tccatgcact catccatgat aatagcaatg gggccgtggg 4500 cagcggcgcg ggcaaacacg ttccgtgggt ctgacacatc atagttatgt tcctgagtta 4560 aatcatcata agccatttta atgaatttgg ggcggagagt accagattgg ggtatgaatg 4620 ttccttcggg ccccggagca tagttcccct cacagatttg catttcccaa gctttcagtt 4680 ccgagggtgg aatcatgtcc acctgggggg ctatgaaaaa caccgtttct ggggcggggg 4740 tgattaattg tgatgatagc aaatttctga gcaattgaga tttgccacat ccggtggggc 4800 cataaatgat tccgattacg ggttgcaggt ggtagtttag ggaacggcaa ctgccgtctt 4860 ctcgaagcaa gggggccacc tcgttcatca tttcccttac atgcatattt tcccgcacca 4920 aatccattag gaggcgctct cctcctagtg atagaagttc ttgtagtgag gaaaagtttt 4980 tcagcggttt cagaccgtca gccatgggca ttttggagag agtttgctgc aaaagttcta 5040 gtctgttcca cagttcagtg atgtgttcta tggcatctcg atccagcaga cctcctcgtt 5100 tcgcgggttt ggacggctcc tggaataggg tatgagacga tgggcgtcca gcgctgccag 5160 ggttcggtcc ttccagggtc tcagtgttcg agtcagggtt gtttccgtca cagtgaaggg 5220 gtgtgcgcct gcttgggcgc ttgccagggt gcgcttcaga ctcatcctgc tggtcgaaaa 5280 cttctgtcgc ttggcgccct gtatgtcggc caagtagcag tttaccatga gttcgtagtt 5340 gagcgcctcg gctgcgtggc ctttggcgcg gagcttacct ttggaagttt tcttgcatac 5400 cgggcagtat aggcatttca gcgcatacaa cttgggcgca aggaaaacgg attctgggga 5460 gtatgcatct gcgccgcagg aggcgcaaac agtttcacat tccaccagcc aggttaaatc 5520 cggttcattg gggtcaaaaa caagttttcc gccatatttt ttgatgcgtt tcttaccttt 5580 ggtctccatg agttcgtgtc ctcgttgagt gacaaacagg ctgtccgtgt ccccgtagac 5640 tgattttaca ggcctcttct ccagtggagt gcctcggtct tcttcgtaca ggaactctga 5700 ccactctgat acaaaggcgc gcgtccaggc cagcacaaag gaggctatgt gggaggggta 5760 gcgatcgttg tcaaccaggg ggtccacctt ttccaaagta tgcaaacaca tgtcaccctc 5820 ttcaacatcc aggaatgtga ttggcttgta ggtgtatttc acgtgacctg gggtccccgc 5880 tgggggggta taaaaggggg cggttctttg ctcttcctca ctgtcttccg gatcgctgtc 5940 caggaacgtc agctgttggg gtaggtattc cctctcgaag gcgggcatga cctctgcact 6000 caggttgtca gtttctaaga acgaggagga tttgatattg acagtgccgg ttgagatgcc 6060 tttcatgagg ttttcgtcca tctggtcaga aaacacaatt tttttattgt caagtttggt 6120 ggcaaatgat ccatacaggg cgttggataa aagtttggca atggatcgca tggtttggtt 6180 cttttccttg tccgcgcgct ctttggcggc gatgttgagt tggacatact cgcgtgccag 6240 gcacttccat tcggggaaga tagttgttaa ttcatctggc acgattctca cttgccaccc 6300 tcgattatgc aaggtaatta aatccacact ggtggccacc tcgcctcgaa ggggttcatt 6360 ggtccaacag agcctacctc ctttcctaga acagaaaggg ggaagtgggt ctagcataag 6420 ttcatcggga gggtctgcat ccatggtaaa gattcccgga agtaaatcct tatcaaaata 6480 gctgatggga gtggggtcat ctaaggccat ttgccattct cgagctgcca gtgcgcgctc 6540 atatgggtta aggggactgc cccatggcat gggatgggtg agtgcagagg catacatgcc 6600 acagatgtca tagacgtaga tgggatcctc aaagatgcct atgtaggttg gatagcatcg 6660 cccccctctg atacttgctc gcacatagtc atatagttca tgtgatggcg ctagcagccc 6720 cggacccaag ttggtgcgat tgggtttttc tgttctgtag acgatctggc gaaagatggc 6780 gtgagaattg gaagagatgg tgggtctttg aaaaatgttg aaatgggcat gaggtagacc 6840 tacagagtct ctgacaaagt gggcataaga ttcttgaagc ttggttacca gttcggcggt 6900 gacaagtacg tctagggcgc agtagtcaag tgtttcttga atgatgtcat aacctggttg 6960 gtttttcttt tcccacagtt cgcggttgag aaggtattct tcgcgatcct tccagtactc 7020 ttctagcgga aacccgtctt tgtctgcacg gtaagatcct agcatgtaga actgattaac 7080 tgccttgtaa gggcagcagc ccttctctac gggtagagag tatgcttgag cagcttttcg 7140 tagcgaagcg tgagtaaggg caaaggtgtc tctgaccatg actttgagga attggtattt 7200 gaagtcgatg tcgtcacagg ctccctgttc ccagagttgg aagtctaccc gtttcttgta 7260 ggcggggttg ggcaaagcga aagtaacatc attgaagaga atcttgccgg ccctgggcat 7320 gaaattgcga gtgatgcgaa aaggctgtgg tacttccgct cggttattga taacctgggc 7380 agctaggacg atctcgtcga aaccgttgat gttgtgtcct acgatgtata attctatgaa 7440 acgcggcgtg cctctgacgt gaggtagctt actgagctca tcaaaggtta ggtctgtggg 7500 gtcagataag gcgtagtgtt cgagagccca ttcgtgcagg tgaggattcg ctttaaggaa 7560 ggaggaccag aggtccactg ccagtgctgt ttgtaactgg tcccggtact gacgaaaatg 7620 ccgtccgact gccatttttt ctggggtgac gcaatagaag gtttgggggt cctgccgcca 7680 gcgatcccac ttgagtttta tggcgaggtc ataggcgatg ttgacgagcc gctggtctcc 7740 agagagtttc atgaccagca tgaaggggat tagctgcttg ccaaaggacc ccatccaggt 7800 gtaggtttcc acatcgtagg tgagaaagag cctttctgtg cgaggatgag agccaatcgg 7860 gaagaactgg atctcctgcc accagttgga ggaatggctg ttgatgtgat ggaagtagaa 7920 ctccctgcga cgcgccgagc attcatgctt gtgcttgtac agacggccgc agtagtcgca 7980 gcgttgcacg ggttgtatct cgtgaatgag ttgtacctgg cttcccttga cgagaaattt 8040 cagtgggaag ccgaggcctg gcgattgtat ctcgtgcttt actatgttgt ctgcatcggc 8100 ctgttcatct tctgtctcga tggtggtcat gctgacgagc cctcgcggga ggcaagtcca 8160 gacctcggcg cggcaggggc ggagctcgag gacgagagcg cgcaggctgg agctgtccag 8220 ggtcctgaga cgctgcggac tcaggttagt aggcagtgtc aggagattaa cttgcatgat 8280 cttttggagg gcgtgcggga ggttcagata gtacttgatc tcaacgggtc cgttggtgga 8340 gatgtcgatg gcttgcaggg ttccgtgtcc cttgggcgct accaccgtgc ccttgttttt 8400 cattttggac ggcggtggct ctgttgcttc ttgcatgttt agaagcggtg tcgagggcgc 8460 gcaccgggcg gcaggggcgg ctcgggaccc ggcggcatgg ctggcagtgg tacgtcggcg 8520 ccgcgcgcgg gtaggttctg gtactgcgcc ctgagaagac tcgcatgcgc gacgacgcgg 8580 cggttgacat cctggatctg acgcctctgg gtgaaagcta ccggccccgt gagcttgaac 8640 ctgaaagaga gttcaacaga atcaatctcg gtatcgttga cggcggcttg cctaaggatt 8700 tcttgcacgt caccagagtt gtcctggtag gcgatctccg ccatgaactg ctcgatctct 8760 tcctcttgaa gatctccgcg gcccgctctc tcgacggtgg ccgcgaggtc gttggagatg 8820 cgcccaatga gttgagagaa tgcattcatg cccgcctcgt tccagacgcg gctgtagacc 8880 acggccccca cgggatctct cgcgcgcatg accacctggg cgaggttgag ctccacgtgg 8940 cgggtgaaga ccgcatagtt gcataggcgc tggaaaaggt agttgagtgt ggtggcgatg 9000 tgctcggtga cgaagaaata catgatccat cgtctcagcg gcatctcgct gacatcgccc 9060 agagcttcca agcgctccat ggcctcgtag aagtccacgg caaaattaaa aaactgggag 9120 tttcgcgcgg acacggtcaa ctcctcttcc agaagacgga taagttcggc gatggtggtg 9180 cgcacctcgc gctcgaaagc ccctgggatt tcttcctcaa tctcttcttc ttccactaac 9240 atctcttcct cttcaggtgg ggctgcagga ggagggggaa cgcggcgacg ccggcggcgc 9300 acgggcagac ggtcgatgaa tctttcaatg acctctccgc ggcggcggcg catggtttca 9360 gtgacggcgc ggccgttctc gcgcggtcgc agagtaaaaa caccgccgcg catctcctta 9420 aagtggtgac tgggaggttc tccgtttggg agggagaggg cgctgattat acattttatt 9480 aattggcccg tagggactgc acgcagagat ctgatcgtgt caagatccac gggatctgaa 9540 aacctttcga cgaaagcgtc taaccagtca cagtcacaag gtaggctgag tacggcttct 9600 tgtgggcggg ggtggttatg tgttcggtct gggtcttctg tttcttcttc atctcgggaa 9660 ggtgagacga tgctgctggt gatgaaatta aagtaggcag ttctaagacg gcggatggtg 9720 gcgaggagca ccaggtcttt gggtccggct tgctggatac gcaggcgatt ggccattccc 9780 caagcattat cctgacatct agcaagatct ttgtagtagt cttgcatgag ccgttctacg 9840 ggcacttctt cctcacccgt tctgccatgc atacgtgtga gtccaaatcc gcgcattggt 9900 tgtaccagtg ccaagtcagc tacgactctt tcggcgagga tggcttgctg tacttgggta 9960 agggtggctt gaaagtcatc aaaatccaca aagcggtggt aagctcctgt attaatggtg 10020 taagcacagt tggccatgac tgaccagtta actgtctggt gaccagggcg cacgagctcg 10080 gtgtatttaa ggcgcgaata ggcgcgggtg tcaaagatgt aatcgttgca ggtgcgcacc 10140 agatactggt accctataag aaaatgcggc ggtggttggc ggtagagagg ccatcgttct 10200 gtagctggag cgccaggggc gaggtcttcc aacataaggc ggtgatagcc gtagatgtac 10260 ctggacatcc aggtgattcc tgcggcggta gtagaagccc gaggaaactc gcgtacgcgg 10320 ttccaaatgt tgcgtagcgg catgaagtag ttcattgtag gcacggtttg accagtgagg 10380 cgcgcgcagt cattgatgct ctatagacac ggagaaaatg aaagcgttca gcgactcgac 10440 tccgtagcct ggaggaacgt gaacgggttg ggtcgcggtg taccccggtt cgagacttgt 10500 actcgagccg gccggagccg cggctaacgt ggtattggca ctcccgtctc gacccagcct 10560 acaaaaatcc aggatacgga atcgagtcgt tttgctggtt tccgaatggc agggaagtga 10620 gtcctatttt ttttttttgc cgctcagatg catcccgtgc tgcgacagat gcgcccccaa 10680 caacagcccc cctcgcagca gcagcagcag caatcacaaa aggctgtccc tgcaactact 10740 gcaactgccg ccgtgagcgg tgcgggacag cccgcctatg atctggactt ggaagagggc 10800 gaaggactgg cacgtctagg tgcgccttca cccgagcggc atccgcgagt tcaactgaaa 10860 aaagattctc gcgaggcgta tgtgccccaa cagaacctat ttagagacag aagcggcgag 10920 gagccggagg agatgcgagc ttcccgcttt aacgcgggtc gtgagctgcg tcacggtttg 10980 gaccgaagac gagtgttgcg ggacgaggat ttcgaagttg atgaaatgac agggatcagt 11040 cctgccaggg cacacgtggc tgcagccaac cttgtatcgg cttacgagca gacagtaaag 11 100 gaagagcgta acttccaaaa gtcttttaat aatcatgtgc gaaccctgat tgcccgcgaa 11160 gaagttaccc ttggtttgat gcatttgtgg gatttgatgg aagctatcat tcagaaccct 11220 actagcaaac ctctgaccgc ccagctgttt ctggtggtgc aacacagcag agacaatgag 11280 gctttcagag aggcgctgct gaacatcacc gaacccgagg ggagatggtt gtatgatctt 11340 atcaacattc tacagagtat catagtgcag gagcggagcc tgggcctggc cgagaaggtg 11400 gctgccatca attactcggt tttgagcttg ggaaaatatt acgctcgcaa aatctacaag 11460 actccatacg ttcccataga caaggaggtg aagatagatg ggttctacat gcgcatgacg 11520 ctcaaggtct tgaccctgag cgatgatctt ggggtgtatc gcaatgacag aatgcatcgc 11580 gcggttagcg ccagcaggag gcgcgagtta agcgacaggg aactgatgca cagtttgcaa 11640 agagctctga ctggagctgg aaccgagggt gagaattact tcgacatggg agctgacttg 11700 cagtggcagc ctagtcgcag ggctctgagc gccgcgacgg caggatgtga gcttccttac 11760 atagaagagg cggatgaagg cgaggaggaa gagggcgagt acttggaaga ctgatggcac 11820 aacccgtgtt ttttgctaga tggaacagca agcaccggat cccgcaatgc gggcggcgct 11880 gcagagccag ccgtccggca ttaactcctc ggacgattgg acccaggcca tgcaacgtat 11940 catggcgttg acgactcgca accccgaagc ctttagacag caaccccagg ccaaccgtct 12000 atcggccatc atggaagctg tagtgccttc ccgctctaat cccactcatg agaaggtcct 12060 ggccatcgtg aacgcgttgg tggagaacaa agctattcgt ccagatgagg ccggactggt 12120 atacaacgct ctcttagaac gcgtggctcg ctacaacagt agcaatgtgc aaaccaattt 12180 ggaccgtatg ataacagatg tacgcgaagc cgtgtctcag cgcgaaaggt tccagcgtga 12240 tgccaacctg ggttcgctgg tggcgttaaa tgctttcttg agtactcagc ctgctaatgt 12300 gccgcgtggt caacaggatt atactaactt tttaagtgct ttgagactga tggtatcaga 12360 agtacctcag agcgaagtgt atcagtccgg tcctgattac ttctttcaga ctagcagaca 12420 gggcttgcag acggtaaatc tgagccaagc ttttaaaaac cttaaaggtt tgtggggagt 12480 gcatgccccg gtaggagaaa gagcaaccgt gtctagcttg ttaactccga actcccgcct 12540 attattactg ttggtagctc ctttcaccga cagcggtagc atcgaccgta attcctattt 12600 gggttaccta ctaaacctgt atcgcgaagc catagggcaa agtcaggtgg acgagcagac 12660 ctatcaagaa attacccaag tcagtcgcgc tttgggacag gaagacactg gcagtttgga 12720 agccactctg aacttcttgc ttaccaatcg gtctcaaaag atccctcctc aatatgctct 12780 tactgcggag gaggagagga tccttagata tgtgcagcag agcgtgggat tgtttctgat 12840 gcaagagggg gcaactccga ctgcagcact ggacatgaca gcgcgaaata tggagcccag 12900 catgtatgcc agtaaccgac ctttcattaa caaactgctg gactacttgc acagagctgc 12960 cgctatgaac tctgattatt tcaccaatgc catcttaaac ccgcactggc tgcccccacc 13020 tggtttctac acgggcgaat atgacatgcc cgaccctaat gacggatttc tgtgggacga 13080 cgtggacagc gatgtttttt cacctctttc tgatcatcgc acgtggaaaa aggaaggcgg 13140 cgatagaatg cattcttctg catcgctgtc cggggtcatg ggtgctaccg cggctgagcc 13200 cgagtctgca agtccttttc ctagtctacc cttttctcta cacagtgtac gtagcagcga 13260 agtgggtaga ataagtcgcc cgagtttaat gggcgaagag gagtatctaa acgattcctt 13320 gctcagaccg gcaagagaaa aaaatttccc aaacaatgga atagaaagtt tggtggataa 13380 aatgagtaga tggaagactt atgctcagga tcacagagac gagcctggga tcatggggat 13440 tacaagtaga gcgagccgta gacgccagcg ccatgacaga cagaggggtc ttgtgtggga 13500 cgatgaggat tcggccgatg atagcagcgt gctggacttg ggtgggagag gaaggggcaa 13560 cccgtttgct catttgcgcc ctcgcttggg tggtatgttg taaaaaaaaa taaaaaaaaa 13620 actcaccaag gccatggcga cgagcgtacg ttcgttcttc tttattatct gtgtctagta 13680 taatgaggcg agtcgtgcta ggcggagcgg tggtgtatcc ggagggtcct cctccttcgt 13740 acgagagcgt gatgcagcag cagcaggcga cggcggtgat gcaatcccca ctggaggctc 13800 cctttgtgcc tccgcgatac ctggcaccta cggagggcag aaacagcatt cgttattcgg 13860 aactggcacc tcagtacgat accaccaggt tgtatctggt ggacaacaag tcggcggaca 13920 ttgcttctct gaactatcag aatgaccaca gcaacttctt gaccacggtg gtgcaaaaca 13980 atgactttac ccctacggaa gccagcaccc agaccattaa ctttgatgaa cgatcgcggt 14040 ggggcggtca gctaaagacc atcatgcata ctaacatgcc aaacgtgaac gagtatatgt 14100 ttagtaacaa gttcaaagcg cgtgtgatgg tgtccagaaa acctcccgac ggtgctgcag 14160 ttggggatac ttatgatcac aagcaggata ttttgaaata tgagtggttc gagtttactt 14220 tgccagaagg caacttttca gttactatga ctattgattt gatgaacaat gccatcatag 14280 ataattactt gaaagtgggt agacagaatg gagtgcttga aagtgacatt ggtgttaagt 14340 tcgacaccag gaacttcaag ctgggatggg atcccgaaac caagttgatc atgcctggag 14400 tgtatacgta tgaagccttc catcctgaca ttgtcttact gcctggctgc ggagtggatt 14460 ttaccgagag tcgtttgagc aaccttcttg gtatcagaaa aaaacagcca tttcaagagg 14520 gttttaagat tttgtatgaa gatttagaag gtggtaatat tccggccctc ttggatgtag 14580 atgcctatga gaacagtaag aaagaacaaa aagccaaaat agaagctgct acagctgctg 14640 cagaagctaa ggcaaacata gttgccagcg actctacaag ggttgctaac gctggagagg 14700 tcagaggaga caattttgcg ccaacacctg ttccgactgc agaatcatta ttggccgatg 14760 tgtctgaagg aacggacgtg aaactcacta ttcaacctgt agaaaaagat agtaagaata 14820 gaagctataa tgtgttggaa gacaaaatca acacagccta tcgcagttgg tatctttcgt 14880 acaattatgg cgatcccgaa aaaggagtgc gttcctggac attgctcacc acctcagatg 14940 tcacctgcgg agcagagcag gtctactggt cgcttccaga catgatgaag gatcctgtca 15000 ctttccgctc cactagacaa gtcagtaact accctgtggt gggtgcagag cttatgcccg 15060 tcttctcaaa gagcttctac aacgaacaag ctgtgtactc ccagcagctc cgccagtcca 15120 cctcgcttac gcacgtcttc aaccgctttc ctgagaacca gattttaatc cgtccgccgg 15180 cgcccaccat taccaccgtc agtgaaaacg ttcctgctct cacagatcac gggaccctgc 15240 cgttgcgcag cagtatccgg ggagtccaac gtgtgaccgt tactgacgcc agacgccgca 15300 cctgtcccta cgtgtacaag gcactgggca tagtcgcacc gcgcgtcctt tcaagccgca 15360 ctttctaaaa aaaaaaaaaa tgtccattct tatctcgccc agtaataaca ccggttgggg 15420 tctgcgcgct ccaagcaaga tgtacggagg cgcacgcaaa cgttctaccc aacatcctgt 15480 ccgtgttcgc ggacattttc gcgctccatg gggcgccctc aagggccgca ctcgcgttcg 15540 aaccaccgtc gatgatgtaa tcgatcaggt ggttgccgac gcccgtaatt atactcctac 15600 tgcgcctaca tctactgtgg atgcagttat tgacagtgta gtggctgacg ctcgcaacta 15660 tgctcgacgt aagagccggc gaaggcgcat tgccagacgc caccgagcta ccactgccat 15720 gcgagccgca agagctctgc tacgaagagc tagacgcgtg gggcgaagag ccatgcttag 15780 ggcggccaga cgtgcagctt cgggcgccag cgccggcagg tcccgcaggc aagcagccgc 15840 tgtcgcagcg gcgactattg ccgacatggc ccaatcgcga agaggcaatg tatactgggt 15900 gcgtgacgct gccaccggtc aacgtgtacc cgtgcgcacc cgtccccctc gcacttagaa 15960 gatactgagc agtctccgat gttgtgtccc agcggcgagg atgtccaagc gcaaatacaa 16020 ggaagaaatg ctgcaggtta tcgcacctga agtctacggc caaccgttga aggatgaaaa 16080 aaaaccccgc aaaatcaagc gggttaaaaa ggacaaaaaa gaagaggaag atggcgatga 16140 tgggctggcg gagtttgtgc gcgagtttgc cccacggcga cgcgtgcaat ggcgtgggcg 16200 caaagttcga catgtgttga gacctggaac ttcggtggtc tttacacccg gcgagcgttc 16260 aagcgctact tttaagcgtt cctatgatga ggtgtacggg gatgatgata ttcttgagca 16320 ggcggctgac cgattaggcg agtttgctta tggcaagcgt agtagaataa cttccaagga 16380 tgagacagtg tcgataccct tggatcatgg aaatcccacc cctagtctta aaccggtcac 16440 tttgcagcaa gtgttacccg taactccgcg aacaggtgtt aaacgcgaag gtgaagattt 16500 gtatcccact atgcaactga tggtacccaa acgccagaag ttggaggacg ttttggagaa 16560 agtaaaagtg gatccagata ttcaacctga ggttaaagtg agacccatta agcaggtagc 16620 gcctggtctg ggggtacaaa ctgtagacat taagattccc actgaaagta tggaagtgca 16680 aactgaaccc gcaaagccta ctgccacctc cactgaagtg caaacggatc catggatgcc 16740 catgcctatt acaactgacg ccgccggtcc cactcgaaga tcccgacgaa agtacggtcc 16800 agcaagtctg ttgatgccca attatgttgt acacccatct attattccta ctcctggtta 16860 ccgaggcact cgctactatc gcagccgaaa cagtacctcc cgccgtcgcc gcaagacacc 16920 tgcaaatcgc agtcgtcgcc gtagacgcac aagcaaaccg actcccggcg ccctggtgcg 16980 gcaagtgtac cgcaatggta gtgcggaacc tttgacactg ccgcgtgcgc gttaccatcc 17040 gagtatcatc acttaatcaa tgttgccgct gcctccttgc agatatggcc ctcacttgtc 17100 gccttcgcgt tcccatcact ggttaccgag gaagaaactc gcgccgtaga agagggatgt 17160 tgggacgcgg aatgcgacgc tacaggcgac ggcgtgctat ccgcaagcaa ttgcggggtg 17220 gttttttacc agccttaatt ccaattatcg ctgctgcaat tggcgcgata ccaggcatag 17280 cttccgtggc ggttcaggcc tcgcaacgac attgacattg gaaaaaaacg tataaataaa 17340 aaaaaaaaaa tacaatggac tctgacactc ctggtcctgt gactatgttt tcttagagat 17400 ggaagacatc aatttttcat ccttggctcc gcgacacggc acgaagccgt acatgggcac 17460 ctggagcgac atcggcacga gccaactgaa cgggggcgcc ttcaattgga gcagtatctg 17520 gagcgggctt aaaaattttg gctcaaccat aaaaacatac gggaacaaag cttggaacag 17580 cagtacagga caggcgctta gaaataaact taaagaccag aacttccaac aaaaagtagt 17640 cgatgggata gcttccggca tcaatggagt ggtagatttg gctaaccagg ctgtgcagaa 17700 aaagataaac agtcgtttgg acccgccgcc agcaacccca ggtgaaatgc aagtggagga 17760 agaaattcct ccgccagaaa aacgaggcga caagcgtccg cgtcccgatt tggaagagac 17820 gctggtgacg cgcgtagatg aaccgccttc ttatgaggaa gcaacgaagc ttggaatgcc 17880 caccactaga ccgatagccc caatggccac cggggtgatg aaaccttctc agttgcatcg 17940 acccgtcacc ttggatttgc cccctccccc tgctgctact gctgtacccg cttctaagcc 18000 tgtcgctgcc ccgaaaccag tcgccgtagc caggtcacgt cccgggggcg ctcctcgtcc 18060 aaatgcgcac tggcaaaata ctctgaacag catcgtgggt ctaggcgtgc aaagtgtaaa 18 120 acgccgtcgc tgcttttaat taaatatgga gtagcgctta acttgcctat ctgtgtatat 18180 gtgtcattac acgccgtcac agcagcagag gaaaaaagga agaggtcgtg cgtcgacgct 18240 gagttacttt caagatggcc accccatcga tgctgcccca atgggcatac atgcacatcg 18300 ccggacagga tgcttcggag tacctgagtc cgggtctggt gcagttcgcc cgcgccacag 18360 acacctactt caatctggga aataagttta gaaatcccac cgtagcgccg acccacgatg 18420 tgaccaccga ccgtagccag cggctcatgt tgcgcttcgt gcccgttgac cgggaggaca 18480 atacatactc ttacaaagtg cggtacaccc tggccgtggg cgacaacaga gtgctggata 18540 tggccagcac gttctttgac attaggggtg tgttggacag aggtcccagt ttcaaaccct 18600 attctggtac ggcttacaac tccctggctc ctaaaggcgc tccaaataca tctcagtgga 18660 ttgcagaagg tgtaaaaaat acaactggtg aggaacacgt aacagaagag gaaaccaata 18720 ctactactta cacttttggc aatgctcctg taaaagctga agctgaaatt acaaaagaag 18780 gactcccagt aggtttggaa gtttcagatg aagaaagtaa accgatttat gctgataaaa 18840 catatcagcc agaacctcag ctgggagatg aaacttggac tgaccttgat ggaaaaaccg 18900 aaaagtatgg aggcagggct ctcaaacccg atactaagat gaaaccatgc tacgggtcct 18960 ttgccaaacc tactaatgtg aaaggcggtc aggcaaaaca aaaaacaacg gagcagccaa 19020 atcagaaagt cgaatatgat atcgacatgg agttttttga tgcggcatcg cagaaaacaa 19080 acttaagtcc taaaattgtc atgtatgcag aaaatgtaaa tttggaaact ccagacactc 19140 atgtagtgta caaacctgga acagaagaca caagttccga agctaatttg ggacaacaat 19200 ctatgcccaa cagacccaac tacattggct tcagagataa ctttattgga cttatgtact 19260 ataacagtac tggtaacatg ggggtgctgg ctggtcaagc gtctcagtta aatgcagtgg 19320 ttgacttgca ggacagaaac acagaacttt cttaccaact cttgcttgac tctctgggcg 19380 acagaaccag atactttagc atgtggaatc aggctgtgga cagttatgat cctgatgtac 19440 gtgttattga aaatcatggt gtggaagatg aacttcccaa ctactgtttt ccactggacg 19500 gcataggtgt tccaacaacc agttacaaat caatagttcc aaatggagac aatgcgccta 19560 attggaagga acctgaagta aatggaacaa gtgagatcgg acagggtaat ttgtttgcca 19620 tggaaattaa ccttcaagcc aatctatggc gaagtttcct ttattccaat gtggctctat 19680 atctcccaga ctcgtacaaa tacaccccgt ccaatgtcac tcttccagaa aacaaaaaca 19740 cctacgacta catgaacggg cgggtggtgc cgccatctct agtagacacc tatgtgaaca 19800 ttggtgccag gtggtctctg gatgccatgg acaatgtcaa cccattcaac caccaccgta 19860 acgctggctt gcgttaccga tccatgcttc tgggtaacgg acgttatgtg cctttccaca 19920 tacaagtgcc tcaaaaattc ttcgctgtta aaaacctgct gcttctccca ggctcctaca 19980 cttatgagtg gaactttagg aaggatgtga acatggttct acagagttcc ctcggtaacg 20040 acctgcgggt agatggcgcc agcatcagtt tcacgagcat caacctctat gctacttttt 20100 tccccatggc tcacaacacc gcttccaccc ttgaagccat gctgcggaat gacaccaatg 20160 atcagtcatt caacgactac ctatctgcag ctaacatgct ctaccccatt cctgccaatg 20220 caaccaatat tcccatttcc attccttctc gcaactgggc ggctttcaga ggctggtcat 20280 ttaccagact gaaaaccaaa gaaactccct ctttggggtc tggatttgac ccctactttg 20340 tctattctgg ttctattccc tacctggatg gtaccttcta cctgaaccac acttttaaga 20400 aggtttccat catgtttgac tcttcagtga gctggcctgg aaatgacagg ttactatctc 20460 ctaacgaatt tgaaataaag cgcactgtgg atggcgaagg ctacaacgta gcccaatgca 20520 acatgaccaa agactggttc ttggtacaga tgctcgccaa ctacaacatc ggctatcagg 20580 gcttctacat tccagaagga tacaaagatc gcatgtattc atttttcaga aacttccagc 20640 ccatgagcag gcaggtggtt gatgaggtca attacaaaga cttcaaggcc gtcgccatac 20700 cctaccaaca caacaactct ggctttgtgg gttacatggc tccgaccatg cgccaaggtc 20760 aaccctatcc cgctaactat ccctatccac tcattggaac aactgccgta aatagtgtta 20820 cgcagaaaaa gttcttgtgt gacagaacca tgtggcgcat accgttctcg agcaacttca 20880 tgtctatggg ggcccttaca gacttgggac agaatatgct ctatgccaac tcagctcatg 20940 ctctggacat gacctttgag gtggatccca tggatgagcc caccctgctt tatcttctct 21000 tcgaagtttt cgacgtggtc agagtgcatc agccacaccg cggcatcatc gaggcagtct 21060 acctgcgtac accgttctcg gccggtaacg ctaccacgta agaagcttct tgcttcttgc 21120 aaatagcagc tgcaaccatg gcctgcggat cccaaaacgg ctccagcgag caagagctca 21180 gagccattgt ccaagacctg ggttgcggac cctatttttt gggaacctac gataagcgct 21240 tcccggggtt catggccccc gataagctcg cctgtgccat tgtaaatacg gccggacgtg 21300 agacgggggg agagcactgg ttggctttcg gttggaaccc acgttctaac acctgctacc 21360 tttttgatcc ttttggattc tcggatgatc gtctcaaaca gatttaccag tttgaatatg 21420 agggtctcct gcgccgcagc gctcttgcta ccaaggaccg ctgtattacg ctggaaaaat 21480 ctacccagac cgtgcagggt ccccgttctg ccgcctgcgg acttttctgc tgcatgttcc 21540 ttcacgcctt tgtgcactgg cctgaccgtc ccatggacgg aaaccccacc atgaaattgc 21600 taactggagt gccaaacaac atgcttcatt ctcctaaagt ccagcccacc ctgtgtgaca 21660 atcaaaaagc actctaccat tttcttaata cccattcgcc ttattttcgc tcccatcgta 21720 cacacatcga aagggccact gcgttcgacc gtatggatgt tcaataatga ctcatgtaaa 21780 caacgtgttc aataaacatc actttatttt tttacatgta tcaaggctct gcattactta 21840 tttatttaca agtcgaatgg gttctgacga gaatcagaat gacccgcagg cagtgatacg 21900 ttgcggaact gatacttggg ttgccacttg aattcgggaa tcaccaactt gggaaccggt 21960 atatcgggca ggatgtcact ccacagcttt ctggtcagct gcaaagctcc aagcaggtca 22020 ggagccgaaa tcttgaaatc acaattagga ccagtgcttt gagcgcgaga gttgcggtac 22080 accggattgc agcactgaaa caccatcagc gacggatgtc tcacgcttgc cagcacggtg 22140 ggatctgcaa tcatgcccac atccagatct tcagcattgg caatgctgaa cggggtcatc 22200 ttgcaggtct gcctacccat ggcgggcacc caattaggct tgtggttgca atcgcagtgc 22260 agggggatca gtatcatctt ggcctgatcc tgtctgattc ctggatacac ggctctcatg 22320 aaagcatcat attgcttgaa agcctgctgg gctttactac cctcggtata aaacatcccg 22380 caggacctgc tcgaaaactg gttagctgca cagccggcat cattcacaca gcagcgggcg 22440 tcattgttag ctatttgcac cacacttctg ccccagcggt tttgggtgat tttggttcgc 22500 tcgggattct cctttaaggc tcgttgtccg ttctcgctgg ccacatccat ctcgataatc 22560 tgctccttct gaatcataat attgccatgc aggcacttca gcttgccctc ataatcattg 22620 cagccatgag gccacaacgc acagcctgta cattcccaat tatggtgggc gatctgagaa 22680 aaagaatgta tcattccctg cagaaatctt cccatcatcg tgctcagtgt cttgtgacta 22740 gtgaaagtta actggatgcc tcggtgctcc tcgtttacgt actggtgaca gatgcgcttg 22800 tattgttcgt gttgctcagg cattagttta aaagaggttc taagttcgtt atccagcctg 22860 tacttctcca tcagcagaca catcacttcc atgcctttct cccaagcaga caccaggggc 22920 aagctaatcg gattcttaac agtgcaggca gcagctcctt tagccagagg gtcatcttta 22980 gcgatcttct caatgcttct tttgccatcc ttctcaacga tgcgcacggg cgggtagctg 23040 aaacccactg ctacaagttg cgcctcttct ctttcttctt cgctgtcttg actgatgtct 23100 tgcatgggga tatgtttggt cttccttggc ttctttttgg ggggtatcgg aggaggagga 23160 ctgtcgctcc gttccggaga cagggaggat tgtgacgttt cgctcaccat taccaactga 23220 ctgtcggtag aagaacctga ccccacacgg cgacaggtgt ttctcttcgg gggcagaggt 23280 ggaggcgatt gcgaagggct gcggtccgac ctggaaggcg gatgactggc agaacccctt 23340 ccgcgttcgg gggtgtgctc cctgtggcgg tcgcttaact gatttccttc gcggctggcc 23400 attgtgttct cctaggcaga gaaacaacag acatggaaac tcagccattg ctgtcaacat 23460 cgccacgagt gccatcacat ctcgtcctca gcgacgagga aaaggagcag agcttaagca 23520 ttccaccgcc cagtcctgcc accacctcta ccctagaaga taaggaggtc gacgcatctc 23580 atgacatgca gaataaaaaa gcgaaagagt ctgagacaga catcgagcaa gacccgggct 23640 atgtgacacc ggtggaacac gaggaagagt tgaaacgctt tctagagaga gaggatgaaa 23700 actgcccaaa acaacgagca gataactatc accaagatgc tggaaatagg gatcagaaca 23760 ccgactacct catagggctt gacggggaag acgcgctcct taaacatcta gcaagacagt 23820 cgctcatagt caaggatgca ttattggaca gaactgaagt gcccatcagt gtggaagagc 23880 tcagccgcgc ctacgagctt aacctctttt cacctcgtac tccccccaaa cgtcagccaa 23940 acggcacctg cgagccaaat cctcgcttaa acttttatcc agcttttgct gtgccagaag 24000 tactggctac ctatcacatc ttttttaaaa atcaaaaaat tccagtctcc tgccgcgcta 24060 atcgcacccg cgccgatgcc ctactcaatc tgggacctgg ttcacgctta cctgatatag 24120 cttccttgga agaggttcca aagatcttcg agggtctggg caataatgag actcgggccg 24180 caaatgctct gcaaaaggga gaaaatggca tggatgagca tcacagcgtt ctggtggaat 24 240 tggaaggcga taatgccaga ctcgcagtac tcaagcgaag catcgaggtc acacacttcg 24300 catatcccgc tgtcaacctg ccccctaaag tcatgacggc ggtcatggac cagttactca 24360 ttaagcgcgc aagtcccctt tcagaagaca tgcatgaccc agatgcctgt gatgagggta 24420 aaccagtggt cagtgatgag cagctaaccc gatggctggg caccgactct cccagggatt 24480 tggaagagcg tcgcaagctt atgatggccg tggtgctggt taccgtagaa ctagagtgtc 24540 tccgacgttt ctttaccgat tcagaaacct tgcgcaaact cgaagagaat ctgcactaca 24600 cttttagaca cggctttgtg cggcaggcat gcaagatatc taacgtggaa ctcaccaacc 24660 tggtttccta catgggtatt ctgcatgaga atcgcctagg acaaagcgtg ctgcacagca 24720 ccctgaaggg ggaagcccgc cgtgattaca tccgcgattg tgtctatctg tacctgtgcc 24780 acacgtggca aaccggcatg ggtgtatggc agcaatgttt agaagaacag aacttgaaag 24840 agcttgacaa gctcttacag aaatctctta aggttctgtg gacagggttc gacgagcgca 24900 ccgtcgcttc cgacctggca gacctcatct tcccagagcg tctcagggtt actttgcgaa 24960 acggattgcc tgactttatg agccagagca tgcttaacaa ttttcgctct ttcatcctgg 25020 aacgctccgg tatcctgccc gccacctgct gcgcactgcc ctccgacttt gtgcctctca 25080 cctaccgcga gtgccccccg ccgctatgga gtcactgcta cctgttccgt ctggccaact 25 140 atctctccta ccactcggat gtgatcgagg atgtgagcgg agacggcttg ctggagtgtc 25200 actgccgctg caatctgtgc acgccccacc ggtccctagc ttgcaacccc cagttgatga 25260 gcgaaaccca gataataggc acctttgaat tgcaaggccc cagcagccaa ggcgatgggt 25320 cttctcctgg gcaaagttta aaactgaccc cgggactgtg gacctccgcc tacttgcgca 25380 agtttgctcc ggaagattac cacccctatg aaatcaagtt ctatgaggac caatcacagc 25440 ctccaaaggc cgaactttcg gcctgcgtca tcacccaggg ggcaattctg gcccaattgc 25500 aagccatcca aaaatcccgc caagaatttc tactgaaaaa gggtaagggg gtctaccttg 25560 acccccagac cggcgaggaa ctcaacacaa ggttccctca ggatgtccca acgacgagaa 25620 aacaagaagt tgaaggtgca gccgccgccc ccagaagata tggaggaaga ttgggacagt 25680 caggcagagg aggcggagga ggacagtctg gaggacagtc tggaggaaga cagtttggag 25740 gaggaaaacg aggaggcaga ggaggtggaa gaagtaaccg ccgacaaaca gttatcctcg 25800 gctgcggaga caagcaacag cgctaccatc tccgctccga gtcgaggaac ccggcggcgt 25860 cccagcagta gatgggacga gaccggacgc ttcccgaacc caaccagcgc ttccaagacc 25920 ggtaagaagg atcggcaggg atacaagtcc tggcgggggc ataagaatgc catcatctcc 25980 tgcttgcatg agtgcggggg caacatatcc ttcacgcggc gctacttgct attccaccat 26040 ggggtgaact ttccgcgcaa tgttttgcat tactaccgtc acctccacag cccctactat 26100 agccagcaaa tcccggcagt ctcgacagat aaagacagcg gcggcgacct ccaacagaaa 26160 accagcagcg gcagttagaa aatacacaac aagtgcagca acaggaggat taaagattac 26220 agccaacgag ccagcgcaaa cccgagagtt aagaaatcgg atctttccaa ccctgtatgc 26280 catcttccag cagagtcggg gtcaagagca ggaactgaaa ataaaaaacc gatctctgcg 26340 ttcgctcacc agaagttgtt tgtatcacaa gagcgaagat caacttcagc gcactctcga 26400 ggacgccgag gctctcttca acaagtactg cgcgctgact cttaaagagt aggcagcgac 26460 cgcgcttatt caaaaaaggc gggaattaca tcatcctcga catgagtaaa gaaattccca 26520 cgccttacat gtggagttat caaccccaaa tgggattggc ggcaggcgcc tcccaggact 26580 actccacccg catgaattgg ctcagcgccg ggccttctat gatttctcga gttaatgata 26640 tacgcgccta ccgaaaccaa atacttttgg aacagtcagc tcttaccacc acgccccgcc 26700 aacaccttaa tcccagaaat tggcccgccg ccctagtgta ccaggaaagt cccgctccca 26760 ccactgtatt acttcctcga gacgcccagg ccgaagtcca aatgactaat gcaggtgcgc 26820 agttagctgg cggctccacc ctatgtcgtc acaggcctcg gcataatata aaacgcctga 26880 tgatcagagg ccgaggtatc cagctcaacg acgagtcggt gagctctccg cttggtctac 26940 gaccagacgg aatctttcag attgccggct gcgggagatc ttccttcacc cctcgtcagg 27000 ctgttctgac tttggaaagt tcgtcttcgc aaccccgctc gggcggaatc gggaccgttc 27060 aatttgtgga ggagtttact ccctctgtct acttcaaccc cttctccgga tctcctgggc 27120 attacccgga cgagttcata ccgaacttcg acgcgattag cgagtcagtg gacggctacg 27180 attgatgtct ggtgacgcgg ctgagctatc tcggctgcga catctagacc actgccgccg 27240 ctttcgctgc tttgcccggg aactcattga gttcatctac ttcgaactcc ccaaggatca 27300 ccctcaaggt ccggcccacg gagtgcggat ttctatcgaa ggcaaaatag actctcgcct 27360 gcaacgaatt ttctcccagc ggcccgtgct gatcgagcga gaccagggaa acaccacggt 27420 ttccatctac tgcatttgta atcaccccgg attgcatgaa agcctttgct gtcttatgtg 27480 tactgagttt aataaaaact gaattaagac tctcctacgg actgccgctt cttcaacccg 27540 gattttacaa ccagaagaac gaaacttttc ctgtcgtcca ggactctgtt aacttcacct 27600 ttcctactca caaactagaa gctcaacgac tacaccgctt ttccagaagc attttcccta 27660 ctaatactac tttcaaaacc ggaggtgagc tccaaggtct tcctacagaa aacccttggg 27720 tggaagcggg ccttgtagtg ctaggaattc ttgcgggtgg gcttgtgatt attctttgct 27780 acctatacac accttgcttc actttcttag tggtgttgtg gtattggttt aaaaaatggg 27840 gcccatacta gtcttgcttg ttttactttc gcttttggaa ccgggttctg ccaattacga 27900 tccatgtcta gacttcgacc cagaaaactg cacacttact tttgcacccg acacaagccg 27960 catctgtgga gttcatcgcc tctcttacga acttggcccc caacgacaaa aatttacctg 28020 catggtggga atcaacccca tagttatcac ccagcaaagt ggagatacta agggttgcat 28080 tcactgctcc tgcgattcca tcgagtgcac ctacaccctg ctgaagaccc tatgcggcct 28140 aagagacctg ctaccaatga attaaaaaat gattaataaa aaatcactta cttgaaatca 28200 gcaataaggt ctctgttgaa attttctccc agcagcacct cacttccctc ttcccaactc 28260 tggtattcta aaccccgttc agcggcatac tttctccata ctttaaaggg gatgtcaaat 28320 tttagctcct ctcctgtacc cacaatcttc atgtctttct tcccagatga ccaagagagt 28380 ccggctcagt gactccttca accctgtcta cccctatgaa gatgaaagca cctcccaaca 28440 cccctttata aacccagggt ttatttcccc aaatggcttc acacaaagcc caaacggagt 28500 tcttacttta aaatgtttaa ccccactaac aaccacaggc ggatctctac agctaaaagt 28560 gggaggggga cttacagtgg atgacaccaa cggttttttg aaagaaaaca taagtgccac 28620 cacaccactc gttaagactg gtcactctat aggtttacca ctaggagccg gattgggaac 28680 gaatgaaaat aaactttgta tcaaattagg acaaggactt acattcaatt caaacaacat 28740 ttgcattgat gacaatatta acaccttatg gacaggagtc aaccccaccg aagccaactg 28800 tcaaatcatg aactccagtg aatctaatga ttgcaaatta attctaacac tagttaaaac 28860 tggagcacta gtcactgcat ttgtttatgt tataggagta tctaacaatt ttaatatgct 28920 aactacacac agaaatataa attttactgc agagctgttt ttcgattcta ctggtaattt 28980 actaactaga ctctcatccc tcaaaactcc acttaatcat aaatcaggac aaaacatggc 29040 tactggtgcc attactaatg ctaaaggttt catgcccagc acgactgcct atcctttcaa 29100 tgataattct agagaaaaag aaaactacat ttacggaact tgttactaca cagctagtga 29160 tcgcactgct tttcccattg acatatctgt catgcttaac cgaagagcaa taaatgacga 29220 gacatcatat tgtattcgta taacttggtc ctggaacaca ggagatgccc cagaggtgca 29280 aacctctgct acaaccctag tcacctcccc atttaccttt tactacatca gagaagacga 29340 ctgacaaata aagtttgcga tcgccaggcc accatgacag tgctggcgcc agcctggagc 29400 ccaacaacct atctcctcct gctgctgctg ctgagctcgg gactcagtgg gacccaggac 29460 tgctccttcc aacacagccc catctcctcc gacttcgctg tcaaaatccg tgagctgtct 29520 gactacctgc ttcaagatta cccagtcacc gtggcctcca acctccagga cgaggagctc 29580 tgcgggggcc tctggcggct ggtcctggca cagcgctgga tggagcggct caagactgtc 29640 gctgggtcca agatgcaagg cttgctggag cgcgtgaaca cggagataca ctttgtcacc 29700 aaatgtgcct ttcagccccc ccccagctgt cttcgcttcg tccagaccaa catctcccgc 29760 ctcctacagg agacctccga gcagctggtg gcgctgaagc cctggatcac tcgccagaac 29820 ttctcccggt gcctggagct gcagtgtcag cccgactcct caaccctgcc acccccatgg 29880 agtccccggc ccctggaggc cacagccccg ggaagcggag ctactaactt cagcctgctg 29940 aagcaggctg gagacgtgga ggagaaccct ggacctcagg tctccactgc tgcccttgcc 30000 gtcctcctct gcaccatggc tctctgcaac caggtcctct ctgcaccact tgctgctgac 30060 acgccgaccg cctgctgctt cagctacacc tcccgacaga ttccacagaa tttcatagct 30120 gactactttg agacgagcag ccagtgctcc aagcccagtg tcatcttcct aaccaagaga 30180 ggccggcagg tctgtgctga ccccagtgag gagtgggtcc agaaatacgt cagtgacctg 30240 gagctgagtg ccggaagcgg agagggcaga ggaagtctgc taacatgcgg tgacgtcgag 30300 gagaatcctg gacctggcca cacacggagg cagggaacat caccatccaa gtgtccatac 30360 ctcaatttct ttcagctctt ggtgctggct ggtctttctc acttctgttc aggtgttatc 30420 cacgtgacca aggaagtgaa agaagtggca acgctgtcct gtggtcacaa tgtttctgtt 30480 gaagagctgg cacaaactcg catctactgg caaaaggaga agaaaatggt gctgactatg 30540 atgtctgggg acatgaatat atggcccgag tacaagaacc ggaccatctt tgatatcact 30600 aataacctct ccattgtgat cctggctctg cgcccatctg acgagggcac atacgagtgt 30660 gttgttctga agtatgaaaa agacgctttc aagcgggaac acctggctga agtgacgtta 30720 tcagtcaaag ctgacttccc tacacctagt atatctgact ttgaaattcc aacttctaat 30780 attagaagga taatttgctc aacctctgga ggttttccag agcctcacct ctcctggttg 30840 gaaaatggag aagaattaaa tgccatcaac acaacagttt cccaagatcc tgaaactgag 30900 ctctatgctg ttagcagcaa actggatttc aatatgacaa ccaaccacag cttcatgtgt 30960 ctcatcaagt atggacattt aagagtgaat cagaccttca actggaatac aaccaagcaa 31020 gagcattttc ctgataacct gctcccatcc tgggccatta ccttaatctc agtaaatgga 31080 atttttgtga tatgctgcct gacctactgc tttgccccaa gatgcagaga gagaaggagg 31140 aatgagagat tgagaaggga aagtgtacgc cctgtataag ctagcttgac tgactgagat 31200 acagcgtacc ttcagctcac agacatgata agatacattg atgagtttgg acaaaccaca 31260 actagaatgc agtgaaaaaa atgctttatt tgtgaaattt gtgatgctat tgctttattt 31320 gtaaccatta taagctgcaa taaacaagtt aacaacaaca attgcattca ttttatgttt 31380 caggttcagg gggaggtgtg ggaggttttt taaagcaagt aaaacctcta caaatgtggt 31440 agtcgtcagc tatcctgcag gaacttgttt atttgaaaat caattcacaa aatccgagta 31500 gttattttgc ctcccccttc ccatttaaca gaatacacca atctctcccc acgcacagct 31560 ttaaacattt ggataccatt agatatagac atggttttag attccacatt ccaaacagtt 31620 tcagagcgag ccaatctggg gtcagtgata gataaaaatc catcgggata gtcttttaaa 31680 gcgctttcac agtccaactg ctgcggatgc gactccggag tctggatcac ggtcatctgg 31740 aagaagaacg atgggaatca taatccgaaa acggtatcgg acgattgtgt ctcatcaaac 31800 ccacaagcag ccgctgtctg cgtcgctccg tgcgactgct gtttatggga tcagggtcca 31860 cagtgtcctg aagcatgatt ttaatagccc ttaacatcaa ctttctggtg cgatgcgcgc 31920 agcaacgcat tctgatttca ctcaaatctt tgcagtaggt acaacacatt attacaatat 31980 tgtttaataa accataatta aaagcgctcc agccaaaact catatctgat ataatcgccc 32040 ctgcatgacc atcataccaa agtttaatat aaattaaatg acgttccctc aaaaacacac 32 100 tacccacata catgatctct tttggcatgt gcatattaac aatctgtctg taccatggac 32160 aacgttggtt aatcatgcaa cccaatataa ccttccggaa ccacactgcc aacaccgctc 32220 ccccagccat gcattgaagt gaaccctgct gattacaatg acaatgaaga acccaattct 32280 ctcgaccgtg aatcacttga gaatgaaaaa tatctatagt ggcacaacat agacataaat 32340 gcatgcatct tctcataatt tttaactcct caggatttag aaacatatcc cagggaatag 32400 gaagctcttg cagaacagta aagctggcag aacaaggaag accacgaaca caacttacac 32460 tatgcatagt catagtatca caatctggca acagcgggtg gtcttcagtc atagaagctc 32520 gggtttcatt ttcctcacaa cgtggtaact gggctctggt gtaagggtga tgtctggcgc 32580 atgatgtcga gcgtgcgcgc aaccttgtca taatggagtt gcttcctgac attctcgtat 32640 tttgtatagc aaaacgcggc cctggcagaa cacactcttc ttcgccttct atcctgccgc 32700 ttagcgtgtt ccgtgtgata gttcaagtac aaccacactc ttaagttggt caaaagaatg 32760 ctggcttcag ttgtaatcaa aactccatcg catctaatcg ttctgaggaa atcatccaag 32820 caatgcaact ggattgtgtt tcaagcagga gaggagaggg aagagacgga agaaccatgt 32880 taatttttat tccaaacgat ctcgcagtac ttcaaattgt agatcgcgca gatggcatct 32940 ctcgccccca ctgtgttggt gaaaaagcac agctagatca aaagaaatgc gattttcaag 33000 gtgctcaacg gtggcttcca gcaaagcctc cacgcgcaca tccaagaaca aaagaatacc 33060 aaaagaagga gcattttcta actcctcaat catcatatta cattcctgca ccattcccag 33 120 ataattttca gctttccagc cttgaattat tcgtgtcagt tcttgtggta aatccaatcc 33180 acacattaca aacaggtccc ggagggcgcc ctccaccacc attcttaaac acaccctcat 33240 aatgacaaaa tatcttgctc ctgtgtcacc tgtagcgaat tgagaatggc aacatcaatt 33300 gacatgccct tggctctaag ttcttcttta agttctagtt gtaaaaactc tctcatatta 33360 tcaccaaact gcttagccag aagccccccg ggaacaagag caggggacgc tacagtgcag 33420 tacaagcgca gacctcccca attggctcca gcaaaaacaa gattggaata agcatattgg 33480 gaaccgccag taatatcatc gaagttgctg gaaatataat caggcagagt ttcttgtaaa 33540 aattgaataa aagaaaaatt tgccaaaaaa acattcaaaa cctctgggat gcaaatgcaa 33600 taggttaccg cgctgcgctc caacattgtt agttttgaat tagtctgcaa aaataaaaaa 33660 aaaaacaagc gtcatatcat agtagcctga cgaacagatg gataaatcag tctttccatc 33720 acaagacaag ccacagggtc tccagctcga ccctcgtaaa acctgtcatc atgattaaac 33780 aacagcaccg aaagttcctc gcggtgacca gcatgaataa ttcttgatga agcatacaat 33840 ccagacatgt tagcatcagt taacgagaaa aaacagccaa catagccttt gggtataatt 33900 atgcttaatc gtaagtatag caaagccacc cctcgcggat acaaagtaaa aggcacagga 33960 gaataaaaaa tataattatt tctctgctgc tgttcaggca acgtcgcccc cggtccctct 34020 aaatacacat acaaagcctc atcagccatg gcttaccaga caaagtacag cgggcacaca 34080 aagcacaagc tctaaagtga ctctccaacc tctccacaat atatatatac acaagcccta 34 140 aactgacgta atgggagtaa agtgtaaaaa atcccgccaa acccaacaca caccccgaaa 34200 ctgcgtcacc agggaaaagt acagtttcac ttccgcaatc ccaacaggcg taacttcctc 34260 tttctcacgg tacgtgatat cccactaact tgcaacgtca ttttcccacg gtcgcaccgc 34320 cccttttagc cgttaacccc acagccaatc accacacgat ccacactttt taaaatcacc 34380 tcatttacat attggcacca ttccatctat aaggtatatt atatagatag ga 34432 <210> 20 <211> 34458 <212> DNA <213> Artificial Sequence <220> <223> NG-347 virus genome sequence comprising a transgene cassette encoding IFNa, MIP1a and CD80, employing SSA and a P2A sequence, inserted in the region BY <400> 20 tctatctata taatatacct tatagatgga atggtgccaa tatgtaaatg aggtgatttt 60 aaaaagtgtg gatcgtgtgg tgattggctg tggggttaac ggctaaaagg ggcggtgcga 120 ccgtgggaaa atgacgtttt gtgggggtgg agtttttttg caagttgtcg cgggaaatgt 180 gacgcataaa aaggcttttt tctcacggaa ctacttagtt ttcccacggt atttaacagg 240 aaatgaggta gttttgaccg gatgcaagtg aaaattgttg attttcgcgc gaaaactgaa 300 tgaggaagtg tttttctgaa taatgtggta tttatggcag ggtggagtat ttgttcaggg 360 ccaggtagac tttgacccat tacgtggagg tttcgattac cgtgtttttt acctgaattt 420 ccgcgtaccg tgtcaaagtc ttctgttttt acgtaggtgt cagctgatcg ctagggtatt 480 tatacctcag ggtttgtgtc aagaggccac tcttgagtgc cagcgagaag agttttctcc 540 tctgcgccgg cagtttaata ataaaaaaat gagagatttg cgatttctgc ctcaggaaat 600 aatctctgct gagactggaa atgaaatatt ggagcttgtg gtgcacgccc tgatgggaga 660 cgatccggag ccacctgtgc agctttttga gcctcctacg cttcaggaac tgtatgattt 720 agaggtagag ggatcggagg attctaatga ggaagctgta aatggctttt ttaccgattc 780 tatgctttta gctgctaatg aagggttaga attagatccg cctttggaca cttttgatac 840 tccaggggta attgtggaaa gcggtacagg tgtaagaaaa ttacctgatt tgagttccgt 900 ggactgtgat ttgcactgct atgaagacgg gtttcctccg agtgatgagg aggaccatga 960 aaaggagcag tccatgcaga ctgcagcggg tgagggagtg aaggctgcca atgttggttt 1020 tcagttggat tgcccggagc ttcctggaca tggctgtaag tcttgtgaat ttcacaggaa 1080 aaatactgga gtaaaggaac tgttatgttc gctttgttat atgagaacgc actgccactt 1140 tatttacagt aagtgtgttt aagttaaaat ttaaaggaat atgctgtttt tcacatgtat 1200 attgagtgtg agttttgtgc ttcttattat aggtcctgtg tctgatgctg atgaatcacc 1260 atctcctgat tctactacct cacctcctga gattcaagca cctgttcctg tggacgtgcg 1320 caagcccatt cctgtgaagc ttaagcctgg gaaacgtcca gcagtggaaa aacttgagga 1380 cttgttacag ggtggggacg gacctttgga cttgagtaca cggaaacgtc caagacaata 1440 agtgttccat atccgtgttt acttaaggtg acgtcaatat ttgtgtgaca gtgcaatgta 1500 ataaaaatat gttaactgtt cactggtttt tattgctttt tgggcgggga ctcaggtata 1560 taagtagaag cagacctgtg tggttagctc ataggagctg gctttcatcc atggaggttt 1620 gggccatttt ggaagacctt aggaagacta ggcaactgtt agagaacgct tcggacggag 1680 tctccggttt ttggagattc tggttcgcta gtgaattagc tagggtagtt tttaggataa 1740 aacaggacta taaacaagaa tttgaaaagt tgttggtaga ttgcccagga ctttttgaag 1800 ctcttaattt gggccatcag gttcacttta aagaaaaagt tttatcagtt ttagactttt 1860 caaccccagg tagaactgct gctgctgtgg cttttcttac ttttatatta gataaatgga 1920 tcccgcagac tcatttcagc aggggatacg ttttggattt catagccaca gcattgtgga 1980 gaacatggaa ggttcgcaag atgaggacaa tcttaggtta ctggccagtg cagcctttgg 2040 gtgtagcggg aatcctgagg catccaccgg tcatgccagc ggttctggag gaggaacagc 2100 aagaggacaa cccgagagcc ggcctggacc ctccagtgga ggaggcggag tagctgactt 2160 gtctcctgaa ctgcaacggg tgcttactgg atctacgtcc actggacggg ataggggcgt 2220 taagagggag agggcatcta gtggtactga tgctagatct gagttggctt taagtttaat 2280 gagtcgcaga cgtcctgaaa ccatttggtg gcatgaggtt cagaaagagg gaagggatga 2340 agtttctgta ttgcaggaga aatattcact ggaacaggtg aaaacatgtt ggttggagcc 2400 tgaggatgat tgggaggtgg ccattaaaaa ttatgccaag atagctttga ggcctgataa 2460 acagtataag attactagac ggattaatat ccggaatgct tgttacatat ctggaaatgg 2520 ggctgaggtg gtaatagata ctcaagacaa ggcagttatt agatgctgca tgatggatat 2580 gtggcctggg gtagtcggta tggaagcagt aacttttgta aatgttaagt ttaggggaga 2640 tggttataat ggaatagtgt ttatggccaa taccaaactt atattgcatg gttgtagctt 2700 ttttggtttc aacaatacct gtgtagatgc ctggggacag gttagtgtac ggggatgtag 2760 tttctatgcg tgttggattg ccacagctgg cagaaccaag agtcaattgt ctctgaagaa 2820 atgcatattt caaagatgta acctgggcat tctgaatgaa ggcgaagcaa gggtccgcca 2880 ctgcgcttct acagatactg gatgttttat tttgattaag ggaaatgcca gcgtaaagca 2940 taacatgatt tgcggtgctt ccgatgagag gccttatcaa atgctcactt gtgctggtgg 3000 gcattgtaat atgctggcta ctgtgcatat tgtttcccat caacgcaaaa aatggcctgt 3060 ttttgatcac aatgtgatga cgaagtgtac catgcatgca ggtgggcgta gaggaatgtt 3120 tatgccttac cagtgtaaca tgaatcatgt gaaagtgttg ttggaaccag atgccttttc 3180 cagaatgagc ctaacaggaa tttttgacat gaacatgcaa atctggaaga tcctgaggta 3240 tgatgatacg agatcgaggg tacgcgcatg cgaatgcgga ggcaagcatg ccaggttcca 3300 gccggtgtgt gtagatgtga ctgaagatct cagaccggat catttggtta ttgcccgcac 3360 tggagcagag ttcggatcca gtggagaaga aactgactaa ggtgagtatt gggaaaactt 3420 tggggtggga ttttcagatg gacagattga gtaaaaattt gttttttctg tcttgcagct 3480 gtcatgagtg gaaacgcttc ttttaagggg ggagtcttca gcccttatct gacagggcgt 3540 ctcccatcct gggcaggagt tcgtcagaat gttatgggat ctactgtgga tggaagaccc 3600 gtccaacccg ccaattcttc aacgctgacc tatgctactt taagttcttc acctttggac 3660 gcagctgcag ctgccgccgc cgcttctgtt gccgctaaca ctgtgcttgg aatgggttac 3720 tatggaagca tcatggctaa ttccacttcc tctaataacc cttctaccct gactcaggac 3780 aagttacttg tccttttggc ccagctggag gctttgaccc aacgtctggg tgaactttct 3840 cagcaggtgg tcgagttgcg agtacaaact gagtctgctg tcggcacggc aaagtctaaa 3900 taaaaaaatc ccagaatcaa tgaataaata aacaagcttg ttgttgattt aaaatcaagt 3960 gtttttattt catttttcgc gcacggtatg ccctagacca ccgatctcta tcattgagaa 4020 ctcggtggat tttttccagg atcctataga ggtgggattg aatgtttaga tacatgggca 4080 ttaggccgtc tttggggtgg agatagctcc attgaaggga ttcatgctcc ggggtagtgt 4140 tgtaaatcac ccagtcataa caaggtcgca gtgcatggtg ttgcacaata tcttttagaa 4200 gtaggctgat tgccacagat aagcccttgg tgtaggtgtt tacaaaccgg ttgagctggg 4260 atgggtgcat tcggggtgaa attatgtgca ttttggattg gatttttaag ttggcaatat 4320 tgccgccaag atcccgtctt gggttcatgt tatgaaggac caccaagacg gtgtatccgg 4380 tacatttagg aaatttatcg tgcagcttgg atggaaaagc gtggaaaaat ttggagacac 4440 ccttgtgtcc tccaagattt tccatgcact catccatgat aatagcaatg gggccgtggg 4500 cagcggcgcg ggcaaacacg ttccgtgggt ctgacacatc atagttatgt tcctgagtta 4560 aatcatcata agccatttta atgaatttgg ggcggagagt accagattgg ggtatgaatg 4620 ttccttcggg ccccggagca tagttcccct cacagatttg catttcccaa gctttcagtt 4680 ccgagggtgg aatcatgtcc acctgggggg ctatgaaaaa caccgtttct ggggcggggg 4740 tgattaattg tgatgatagc aaatttctga gcaattgaga tttgccacat ccggtggggc 4800 cataaatgat tccgattacg ggttgcaggt ggtagtttag ggaacggcaa ctgccgtctt 4860 ctcgaagcaa gggggccacc tcgttcatca tttcccttac atgcatattt tcccgcacca 4920 aatccattag gaggcgctct cctcctagtg atagaagttc ttgtagtgag gaaaagtttt 4980 tcagcggttt cagaccgtca gccatgggca ttttggagag agtttgctgc aaaagttcta 5040 gtctgttcca cagttcagtg atgtgttcta tggcatctcg atccagcaga cctcctcgtt 5100 tcgcgggttt ggacggctcc tggaataggg tatgagacga tgggcgtcca gcgctgccag 5160 ggttcggtcc ttccagggtc tcagtgttcg agtcagggtt gtttccgtca cagtgaaggg 5220 gtgtgcgcct gcttgggcgc ttgccagggt gcgcttcaga ctcatcctgc tggtcgaaaa 5280 cttctgtcgc ttggcgccct gtatgtcggc caagtagcag tttaccatga gttcgtagtt 5340 gagcgcctcg gctgcgtggc ctttggcgcg gagcttacct ttggaagttt tcttgcatac 5400 cgggcagtat aggcatttca gcgcatacaa cttgggcgca aggaaaacgg attctgggga 5460 gtatgcatct gcgccgcagg aggcgcaaac agtttcacat tccaccagcc aggttaaatc 5520 cggttcattg gggtcaaaaa caagttttcc gccatatttt ttgatgcgtt tcttaccttt 5580 ggtctccatg agttcgtgtc ctcgttgagt gacaaacagg ctgtccgtgt ccccgtagac 5640 tgattttaca ggcctcttct ccagtggagt gcctcggtct tcttcgtaca ggaactctga 5700 ccactctgat acaaaggcgc gcgtccaggc cagcacaaag gaggctatgt gggaggggta 5760 gcgatcgttg tcaaccaggg ggtccacctt ttccaaagta tgcaaacaca tgtcaccctc 5820 ttcaacatcc aggaatgtga ttggcttgta ggtgtatttc acgtgacctg gggtccccgc 5880 tgggggggta taaaaggggg cggttctttg ctcttcctca ctgtcttccg gatcgctgtc 5940 caggaacgtc agctgttggg gtaggtattc cctctcgaag gcgggcatga cctctgcact 6000 caggttgtca gtttctaaga acgaggagga tttgatattg acagtgccgg ttgagatgcc 6060 tttcatgagg ttttcgtcca tctggtcaga aaacacaatt tttttattgt caagtttggt 6120 ggcaaatgat ccatacaggg cgttggataa aagtttggca atggatcgca tggtttggtt 6180 cttttccttg tccgcgcgct ctttggcggc gatgttgagt tggacatact cgcgtgccag 6240 gcacttccat tcggggaaga tagttgttaa ttcatctggc acgattctca cttgccaccc 6300 tcgattatgc aaggtaatta aatccacact ggtggccacc tcgcctcgaa ggggttcatt 6360 ggtccaacag agcctacctc ctttcctaga acagaaaggg ggaagtgggt ctagcataag 6420 ttcatcggga gggtctgcat ccatggtaaa gattcccgga agtaaatcct tatcaaaata 6480 gctgatggga gtggggtcat ctaaggccat ttgccattct cgagctgcca gtgcgcgctc 6540 atatgggtta aggggactgc cccatggcat gggatgggtg agtgcagagg catacatgcc 6600 acagatgtca tagacgtaga tgggatcctc aaagatgcct atgtaggttg gatagcatcg 6660 cccccctctg atacttgctc gcacatagtc atatagttca tgtgatggcg ctagcagccc 6720 cggacccaag ttggtgcgat tgggtttttc tgttctgtag acgatctggc gaaagatggc 6780 gtgagaattg gaagagatgg tgggtctttg aaaaatgttg aaatgggcat gaggtagacc 6840 tacagagtct ctgacaaagt gggcataaga ttcttgaagc ttggttacca gttcggcggt 6900 gacaagtacg tctagggcgc agtagtcaag tgtttcttga atgatgtcat aacctggttg 6960 gtttttcttt tcccacagtt cgcggttgag aaggtattct tcgcgatcct tccagtactc 7020 ttctagcgga aacccgtctt tgtctgcacg gtaagatcct agcatgtaga actgattaac 7080 tgccttgtaa gggcagcagc ccttctctac gggtagagag tatgcttgag cagcttttcg 7140 tagcgaagcg tgagtaaggg caaaggtgtc tctgaccatg actttgagga attggtattt 7200 gaagtcgatg tcgtcacagg ctccctgttc ccagagttgg aagtctaccc gtttcttgta 7260 ggcggggttg ggcaaagcga aagtaacatc attgaagaga atcttgccgg ccctgggcat 7320 gaaattgcga gtgatgcgaa aaggctgtgg tacttccgct cggttattga taacctgggc 7380 agctaggacg atctcgtcga aaccgttgat gttgtgtcct acgatgtata attctatgaa 7440 acgcggcgtg cctctgacgt gaggtagctt actgagctca tcaaaggtta ggtctgtggg 7500 gtcagataag gcgtagtgtt cgagagccca ttcgtgcagg tgaggattcg ctttaaggaa 7560 ggaggaccag aggtccactg ccagtgctgt ttgtaactgg tcccggtact gacgaaaatg 7620 ccgtccgact gccatttttt ctggggtgac gcaatagaag gtttgggggt cctgccgcca 7680 gcgatcccac ttgagtttta tggcgaggtc ataggcgatg ttgacgagcc gctggtctcc 7740 agagagtttc atgaccagca tgaaggggat tagctgcttg ccaaaggacc ccatccaggt 7800 gtaggtttcc acatcgtagg tgagaaagag cctttctgtg cgaggatgag agccaatcgg 7860 gaagaactgg atctcctgcc accagttgga ggaatggctg ttgatgtgat ggaagtagaa 7920 ctccctgcga cgcgccgagc attcatgctt gtgcttgtac agacggccgc agtagtcgca 7980 gcgttgcacg ggttgtatct cgtgaatgag ttgtacctgg cttcccttga cgagaaattt 8040 cagtgggaag ccgaggcctg gcgattgtat ctcgtgcttt actatgttgt ctgcatcggc 8100 ctgttcatct tctgtctcga tggtggtcat gctgacgagc cctcgcggga ggcaagtcca 8160 gacctcggcg cggcaggggc ggagctcgag gacgagagcg cgcaggctgg agctgtccag 8220 ggtcctgaga cgctgcggac tcaggttagt aggcagtgtc aggagattaa cttgcatgat 8280 cttttggagg gcgtgcggga ggttcagata gtacttgatc tcaacgggtc cgttggtgga 8340 gatgtcgatg gcttgcaggg ttccgtgtcc cttgggcgct accaccgtgc ccttgttttt 8400 cattttggac ggcggtggct ctgttgcttc ttgcatgttt agaagcggtg tcgagggcgc 8460 gcaccgggcg gcaggggcgg ctcgggaccc ggcggcatgg ctggcagtgg tacgtcggcg 8520 ccgcgcgcgg gtaggttctg gtactgcgcc ctgagaagac tcgcatgcgc gacgacgcgg 8580 cggttgacat cctggatctg acgcctctgg gtgaaagcta ccggccccgt gagcttgaac 8640 ctgaaagaga gttcaacaga atcaatctcg gtatcgttga cggcggcttg cctaaggatt 8700 tcttgcacgt caccagagtt gtcctggtag gcgatctccg ccatgaactg ctcgatctct 8760 tcctcttgaa gatctccgcg gcccgctctc tcgacggtgg ccgcgaggtc gttggagatg 8820 cgcccaatga gttgagagaa tgcattcatg cccgcctcgt tccagacgcg gctgtagacc 8880 acggccccca cgggatctct cgcgcgcatg accacctggg cgaggttgag ctccacgtgg 8940 cgggtgaaga ccgcatagtt gcataggcgc tggaaaaggt agttgagtgt ggtggcgatg 9000 tgctcggtga cgaagaaata catgatccat cgtctcagcg gcatctcgct gacatcgccc 9060 agagcttcca agcgctccat ggcctcgtag aagtccacgg caaaattaaa aaactgggag 9120 tttcgcgcgg acacggtcaa ctcctcttcc agaagacgga taagttcggc gatggtggtg 9180 cgcacctcgc gctcgaaagc ccctgggatt tcttcctcaa tctcttcttc ttccactaac 9240 atctcttcct cttcaggtgg ggctgcagga ggagggggaa cgcggcgacg ccggcggcgc 9300 acgggcagac ggtcgatgaa tctttcaatg acctctccgc ggcggcggcg catggtttca 9360 gtgacggcgc ggccgttctc gcgcggtcgc agagtaaaaa caccgccgcg catctcctta 9420 aagtggtgac tgggaggttc tccgtttggg agggagaggg cgctgattat acattttatt 9480 aattggcccg tagggactgc acgcagagat ctgatcgtgt caagatccac gggatctgaa 9540 aacctttcga cgaaagcgtc taaccagtca cagtcacaag gtaggctgag tacggcttct 9600 tgtgggcggg ggtggttatg tgttcggtct gggtcttctg tttcttcttc atctcgggaa 9660 ggtgagacga tgctgctggt gatgaaatta aagtaggcag ttctaagacg gcggatggtg 9720 gcgaggagca ccaggtcttt gggtccggct tgctggatac gcaggcgatt ggccattccc 9780 caagcattat cctgacatct agcaagatct ttgtagtagt cttgcatgag ccgttctacg 9840 ggcacttctt cctcacccgt tctgccatgc atacgtgtga gtccaaatcc gcgcattggt 9900 tgtaccagtg ccaagtcagc tacgactctt tcggcgagga tggcttgctg tacttgggta 9960 agggtggctt gaaagtcatc aaaatccaca aagcggtggt aagctcctgt attaatggtg 10020 taagcacagt tggccatgac tgaccagtta actgtctggt gaccagggcg cacgagctcg 10080 gtgtatttaa ggcgcgaata ggcgcgggtg tcaaagatgt aatcgttgca ggtgcgcacc 10140 agatactggt accctataag aaaatgcggc ggtggttggc ggtagagagg ccatcgttct 10200 gtagctggag cgccaggggc gaggtcttcc aacataaggc ggtgatagcc gtagatgtac 10260 ctggacatcc aggtgattcc tgcggcggta gtagaagccc gaggaaactc gcgtacgcgg 10320 ttccaaatgt tgcgtagcgg catgaagtag ttcattgtag gcacggtttg accagtgagg 10380 cgcgcgcagt cattgatgct ctatagacac ggagaaaatg aaagcgttca gcgactcgac 10440 tccgtagcct ggaggaacgt gaacgggttg ggtcgcggtg taccccggtt cgagacttgt 10500 actcgagccg gccggagccg cggctaacgt ggtattggca ctcccgtctc gacccagcct 10560 acaaaaatcc aggatacgga atcgagtcgt tttgctggtt tccgaatggc agggaagtga 10620 gtcctatttt ttttttttgc cgctcagatg catcccgtgc tgcgacagat gcgcccccaa 10680 caacagcccc cctcgcagca gcagcagcag caatcacaaa aggctgtccc tgcaactact 10740 gcaactgccg ccgtgagcgg tgcgggacag cccgcctatg atctggactt ggaagagggc 10800 gaaggactgg cacgtctagg tgcgccttca cccgagcggc atccgcgagt tcaactgaaa 10860 aaagattctc gcgaggcgta tgtgccccaa cagaacctat ttagagacag aagcggcgag 10920 gagccggagg agatgcgagc ttcccgcttt aacgcgggtc gtgagctgcg tcacggtttg 10980 gaccgaagac gagtgttgcg ggacgaggat ttcgaagttg atgaaatgac agggatcagt 11040 cctgccaggg cacacgtggc tgcagccaac cttgtatcgg cttacgagca gacagtaaag 11 100 gaagagcgta acttccaaaa gtcttttaat aatcatgtgc gaaccctgat tgcccgcgaa 11160 gaagttaccc ttggtttgat gcatttgtgg gatttgatgg aagctatcat tcagaaccct 11220 actagcaaac ctctgaccgc ccagctgttt ctggtggtgc aacacagcag agacaatgag 11280 gctttcagag aggcgctgct gaacatcacc gaacccgagg ggagatggtt gtatgatctt 11340 atcaacattc tacagagtat catagtgcag gagcggagcc tgggcctggc cgagaaggtg 11400 gctgccatca attactcggt tttgagcttg ggaaaatatt acgctcgcaa aatctacaag 11460 actccatacg ttcccataga caaggaggtg aagatagatg ggttctacat gcgcatgacg 11520 ctcaaggtct tgaccctgag cgatgatctt ggggtgtatc gcaatgacag aatgcatcgc 11580 gcggttagcg ccagcaggag gcgcgagtta agcgacaggg aactgatgca cagtttgcaa 11640 agagctctga ctggagctgg aaccgagggt gagaattact tcgacatggg agctgacttg 11700 cagtggcagc ctagtcgcag ggctctgagc gccgcgacgg caggatgtga gcttccttac 11760 atagaagagg cggatgaagg cgaggaggaa gagggcgagt acttggaaga ctgatggcac 11820 aacccgtgtt ttttgctaga tggaacagca agcaccggat cccgcaatgc gggcggcgct 11880 gcagagccag ccgtccggca ttaactcctc ggacgattgg acccaggcca tgcaacgtat 11940 catggcgttg acgactcgca accccgaagc ctttagacag caaccccagg ccaaccgtct 12000 atcggccatc atggaagctg tagtgccttc ccgctctaat cccactcatg agaaggtcct 12060 ggccatcgtg aacgcgttgg tggagaacaa agctattcgt ccagatgagg ccggactggt 12120 atacaacgct ctcttagaac gcgtggctcg ctacaacagt agcaatgtgc aaaccaattt 12180 ggaccgtatg ataacagatg tacgcgaagc cgtgtctcag cgcgaaaggt tccagcgtga 12240 tgccaacctg ggttcgctgg tggcgttaaa tgctttcttg agtactcagc ctgctaatgt 12300 gccgcgtggt caacaggatt atactaactt tttaagtgct ttgagactga tggtatcaga 12360 agtacctcag agcgaagtgt atcagtccgg tcctgattac ttctttcaga ctagcagaca 12420 gggcttgcag acggtaaatc tgagccaagc ttttaaaaac cttaaaggtt tgtggggagt 12480 gcatgccccg gtaggagaaa gagcaaccgt gtctagcttg ttaactccga actcccgcct 12540 attattactg ttggtagctc ctttcaccga cagcggtagc atcgaccgta attcctattt 12600 gggttaccta ctaaacctgt atcgcgaagc catagggcaa agtcaggtgg acgagcagac 12660 ctatcaagaa attacccaag tcagtcgcgc tttgggacag gaagacactg gcagtttgga 12720 agccactctg aacttcttgc ttaccaatcg gtctcaaaag atccctcctc aatatgctct 12780 tactgcggag gaggagagga tccttagata tgtgcagcag agcgtgggat tgtttctgat 12840 gcaagagggg gcaactccga ctgcagcact ggacatgaca gcgcgaaata tggagcccag 12900 catgtatgcc agtaaccgac ctttcattaa caaactgctg gactacttgc acagagctgc 12960 cgctatgaac tctgattatt tcaccaatgc catcttaaac ccgcactggc tgcccccacc 13020 tggtttctac acgggcgaat atgacatgcc cgaccctaat gacggatttc tgtgggacga 13080 cgtggacagc gatgtttttt cacctctttc tgatcatcgc acgtggaaaa aggaaggcgg 13140 cgatagaatg cattcttctg catcgctgtc cggggtcatg ggtgctaccg cggctgagcc 13200 cgagtctgca agtccttttc ctagtctacc cttttctcta cacagtgtac gtagcagcga 13260 agtgggtaga ataagtcgcc cgagtttaat gggcgaagag gagtatctaa acgattcctt 13320 gctcagaccg gcaagagaaa aaaatttccc aaacaatgga atagaaagtt tggtggataa 13380 aatgagtaga tggaagactt atgctcagga tcacagagac gagcctggga tcatggggat 13440 tacaagtaga gcgagccgta gacgccagcg ccatgacaga cagaggggtc ttgtgtggga 13500 cgatgaggat tcggccgatg atagcagcgt gctggacttg ggtgggagag gaaggggcaa 13560 cccgtttgct catttgcgcc ctcgcttggg tggtatgttg taaaaaaaaa taaaaaaaaa 13620 actcaccaag gccatggcga cgagcgtacg ttcgttcttc tttattatct gtgtctagta 13680 taatgaggcg agtcgtgcta ggcggagcgg tggtgtatcc ggagggtcct cctccttcgt 13740 acgagagcgt gatgcagcag cagcaggcga cggcggtgat gcaatcccca ctggaggctc 13800 cctttgtgcc tccgcgatac ctggcaccta cggagggcag aaacagcatt cgttattcgg 13860 aactggcacc tcagtacgat accaccaggt tgtatctggt ggacaacaag tcggcggaca 13920 ttgcttctct gaactatcag aatgaccaca gcaacttctt gaccacggtg gtgcaaaaca 13980 atgactttac ccctacggaa gccagcaccc agaccattaa ctttgatgaa cgatcgcggt 14040 ggggcggtca gctaaagacc atcatgcata ctaacatgcc aaacgtgaac gagtatatgt 14100 ttagtaacaa gttcaaagcg cgtgtgatgg tgtccagaaa acctcccgac ggtgctgcag 14160 ttggggatac ttatgatcac aagcaggata ttttgaaata tgagtggttc gagtttactt 14220 tgccagaagg caacttttca gttactatga ctattgattt gatgaacaat gccatcatag 14280 ataattactt gaaagtgggt agacagaatg gagtgcttga aagtgacatt ggtgttaagt 14340 tcgacaccag gaacttcaag ctgggatggg atcccgaaac caagttgatc atgcctggag 14400 tgtatacgta tgaagccttc catcctgaca ttgtcttact gcctggctgc ggagtggatt 14460 ttaccgagag tcgtttgagc aaccttcttg gtatcagaaa aaaacagcca tttcaagagg 14520 gttttaagat tttgtatgaa gatttagaag gtggtaatat tccggccctc ttggatgtag 14580 atgcctatga gaacagtaag aaagaacaaa aagccaaaat agaagctgct acagctgctg 14640 cagaagctaa ggcaaacata gttgccagcg actctacaag ggttgctaac gctggagagg 14700 tcagaggaga caattttgcg ccaacacctg ttccgactgc agaatcatta ttggccgatg 14760 tgtctgaagg aacggacgtg aaactcacta ttcaacctgt agaaaaagat agtaagaata 14820 gaagctataa tgtgttggaa gacaaaatca acacagccta tcgcagttgg tatctttcgt 14880 acaattatgg cgatcccgaa aaaggagtgc gttcctggac attgctcacc acctcagatg 14940 tcacctgcgg agcagagcag gtctactggt cgcttccaga catgatgaag gatcctgtca 15000 ctttccgctc cactagacaa gtcagtaact accctgtggt gggtgcagag cttatgcccg 15060 tcttctcaaa gagcttctac aacgaacaag ctgtgtactc ccagcagctc cgccagtcca 15120 cctcgcttac gcacgtcttc aaccgctttc ctgagaacca gattttaatc cgtccgccgg 15180 cgcccaccat taccaccgtc agtgaaaacg ttcctgctct cacagatcac gggaccctgc 15240 cgttgcgcag cagtatccgg ggagtccaac gtgtgaccgt tactgacgcc agacgccgca 15300 cctgtcccta cgtgtacaag gcactgggca tagtcgcacc gcgcgtcctt tcaagccgca 15360 ctttctaaaa aaaaaaaaaa tgtccattct tatctcgccc agtaataaca ccggttgggg 15420 tctgcgcgct ccaagcaaga tgtacggagg cgcacgcaaa cgttctaccc aacatcctgt 15480 ccgtgttcgc ggacattttc gcgctccatg gggcgccctc aagggccgca ctcgcgttcg 15540 aaccaccgtc gatgatgtaa tcgatcaggt ggttgccgac gcccgtaatt atactcctac 15600 tgcgcctaca tctactgtgg atgcagttat tgacagtgta gtggctgacg ctcgcaacta 15660 tgctcgacgt aagagccggc gaaggcgcat tgccagacgc caccgagcta ccactgccat 15720 gcgagccgca agagctctgc tacgaagagc tagacgcgtg gggcgaagag ccatgcttag 15780 ggcggccaga cgtgcagctt cgggcgccag cgccggcagg tcccgcaggc aagcagccgc 15840 tgtcgcagcg gcgactattg ccgacatggc ccaatcgcga agaggcaatg tatactgggt 15900 gcgtgacgct gccaccggtc aacgtgtacc cgtgcgcacc cgtccccctc gcacttagaa 15960 gatactgagc agtctccgat gttgtgtccc agcggcgagg atgtccaagc gcaaatacaa 16020 ggaagaaatg ctgcaggtta tcgcacctga agtctacggc caaccgttga aggatgaaaa 16080 aaaaccccgc aaaatcaagc gggttaaaaa ggacaaaaaa gaagaggaag atggcgatga 16140 tgggctggcg gagtttgtgc gcgagtttgc cccacggcga cgcgtgcaat ggcgtgggcg 16200 caaagttcga catgtgttga gacctggaac ttcggtggtc tttacacccg gcgagcgttc 16260 aagcgctact tttaagcgtt cctatgatga ggtgtacggg gatgatgata ttcttgagca 16320 ggcggctgac cgattaggcg agtttgctta tggcaagcgt agtagaataa cttccaagga 16380 tgagacagtg tcgataccct tggatcatgg aaatcccacc cctagtctta aaccggtcac 16440 tttgcagcaa gtgttacccg taactccgcg aacaggtgtt aaacgcgaag gtgaagattt 16500 gtatcccact atgcaactga tggtacccaa acgccagaag ttggaggacg ttttggagaa 16560 agtaaaagtg gatccagata ttcaacctga ggttaaagtg agacccatta agcaggtagc 16620 gcctggtctg ggggtacaaa ctgtagacat taagattccc actgaaagta tggaagtgca 16680 aactgaaccc gcaaagccta ctgccacctc cactgaagtg caaacggatc catggatgcc 16740 catgcctatt acaactgacg ccgccggtcc cactcgaaga tcccgacgaa agtacggtcc 16800 agcaagtctg ttgatgccca attatgttgt acacccatct attattccta ctcctggtta 16860 ccgaggcact cgctactatc gcagccgaaa cagtacctcc cgccgtcgcc gcaagacacc 16920 tgcaaatcgc agtcgtcgcc gtagacgcac aagcaaaccg actcccggcg ccctggtgcg 16980 gcaagtgtac cgcaatggta gtgcggaacc tttgacactg ccgcgtgcgc gttaccatcc 17040 gagtatcatc acttaatcaa tgttgccgct gcctccttgc agatatggcc ctcacttgtc 17100 gccttcgcgt tcccatcact ggttaccgag gaagaaactc gcgccgtaga agagggatgt 17160 tgggacgcgg aatgcgacgc tacaggcgac ggcgtgctat ccgcaagcaa ttgcggggtg 17220 gttttttacc agccttaatt ccaattatcg ctgctgcaat tggcgcgata ccaggcatag 17280 cttccgtggc ggttcaggcc tcgcaacgac attgacattg gaaaaaaacg tataaataaa 17340 aaaaaaaaaa tacaatggac tctgacactc ctggtcctgt gactatgttt tcttagagat 17400 ggaagacatc aatttttcat ccttggctcc gcgacacggc acgaagccgt acatgggcac 17460 ctggagcgac atcggcacga gccaactgaa cgggggcgcc ttcaattgga gcagtatctg 17520 gagcgggctt aaaaattttg gctcaaccat aaaaacatac gggaacaaag cttggaacag 17580 cagtacagga caggcgctta gaaataaact taaagaccag aacttccaac aaaaagtagt 17640 cgatgggata gcttccggca tcaatggagt ggtagatttg gctaaccagg ctgtgcagaa 17700 aaagataaac agtcgtttgg acccgccgcc agcaacccca ggtgaaatgc aagtggagga 17760 agaaattcct ccgccagaaa aacgaggcga caagcgtccg cgtcccgatt tggaagagac 17820 gctggtgacg cgcgtagatg aaccgccttc ttatgaggaa gcaacgaagc ttggaatgcc 17880 caccactaga ccgatagccc caatggccac cggggtgatg aaaccttctc agttgcatcg 17940 acccgtcacc ttggatttgc cccctccccc tgctgctact gctgtacccg cttctaagcc 18000 tgtcgctgcc ccgaaaccag tcgccgtagc caggtcacgt cccgggggcg ctcctcgtcc 18060 aaatgcgcac tggcaaaata ctctgaacag catcgtgggt ctaggcgtgc aaagtgtaaa 18 120 acgccgtcgc tgcttttaat taaatatgga gtagcgctta acttgcctat ctgtgtatat 18180 gtgtcattac acgccgtcac agcagcagag gaaaaaagga agaggtcgtg cgtcgacgct 18240 gagttacttt caagatggcc accccatcga tgctgcccca atgggcatac atgcacatcg 18300 ccggacagga tgcttcggag tacctgagtc cgggtctggt gcagttcgcc cgcgccacag 18360 acacctactt caatctggga aataagttta gaaatcccac cgtagcgccg acccacgatg 18420 tgaccaccga ccgtagccag cggctcatgt tgcgcttcgt gcccgttgac cgggaggaca 18480 atacatactc ttacaaagtg cggtacaccc tggccgtggg cgacaacaga gtgctggata 18540 tggccagcac gttctttgac attaggggtg tgttggacag aggtcccagt ttcaaaccct 18600 attctggtac ggcttacaac tccctggctc ctaaaggcgc tccaaataca tctcagtgga 18660 ttgcagaagg tgtaaaaaat acaactggtg aggaacacgt aacagaagag gaaaccaata 18720 ctactactta cacttttggc aatgctcctg taaaagctga agctgaaatt acaaaagaag 18780 gactcccagt aggtttggaa gtttcagatg aagaaagtaa accgatttat gctgataaaa 18840 catatcagcc agaacctcag ctgggagatg aaacttggac tgaccttgat ggaaaaaccg 18900 aaaagtatgg aggcagggct ctcaaacccg atactaagat gaaaccatgc tacgggtcct 18960 ttgccaaacc tactaatgtg aaaggcggtc aggcaaaaca aaaaacaacg gagcagccaa 19020 atcagaaagt cgaatatgat atcgacatgg agttttttga tgcggcatcg cagaaaacaa 19080 acttaagtcc taaaattgtc atgtatgcag aaaatgtaaa tttggaaact ccagacactc 19140 atgtagtgta caaacctgga acagaagaca caagttccga agctaatttg ggacaacaat 19200 ctatgcccaa cagacccaac tacattggct tcagagataa ctttattgga cttatgtact 19260 ataacagtac tggtaacatg ggggtgctgg ctggtcaagc gtctcagtta aatgcagtgg 19320 ttgacttgca ggacagaaac acagaacttt cttaccaact cttgcttgac tctctgggcg 19380 acagaaccag atactttagc atgtggaatc aggctgtgga cagttatgat cctgatgtac 19440 gtgttattga aaatcatggt gtggaagatg aacttcccaa ctactgtttt ccactggacg 19500 gcataggtgt tccaacaacc agttacaaat caatagttcc aaatggagac aatgcgccta 19560 attggaagga acctgaagta aatggaacaa gtgagatcgg acagggtaat ttgtttgcca 19620 tggaaattaa ccttcaagcc aatctatggc gaagtttcct ttattccaat gtggctctat 19680 atctcccaga ctcgtacaaa tacaccccgt ccaatgtcac tcttccagaa aacaaaaaca 19740 cctacgacta catgaacggg cgggtggtgc cgccatctct agtagacacc tatgtgaaca 19800 ttggtgccag gtggtctctg gatgccatgg acaatgtcaa cccattcaac caccaccgta 19860 acgctggctt gcgttaccga tccatgcttc tgggtaacgg acgttatgtg cctttccaca 19920 tacaagtgcc tcaaaaattc ttcgctgtta aaaacctgct gcttctccca ggctcctaca 19980 cttatgagtg gaactttagg aaggatgtga acatggttct acagagttcc ctcggtaacg 20040 acctgcgggt agatggcgcc agcatcagtt tcacgagcat caacctctat gctacttttt 20100 tccccatggc tcacaacacc gcttccaccc ttgaagccat gctgcggaat gacaccaatg 20160 atcagtcatt caacgactac ctatctgcag ctaacatgct ctaccccatt cctgccaatg 20220 caaccaatat tcccatttcc attccttctc gcaactgggc ggctttcaga ggctggtcat 20280 ttaccagact gaaaaccaaa gaaactccct ctttggggtc tggatttgac ccctactttg 20340 tctattctgg ttctattccc tacctggatg gtaccttcta cctgaaccac acttttaaga 20400 aggtttccat catgtttgac tcttcagtga gctggcctgg aaatgacagg ttactatctc 20460 ctaacgaatt tgaaataaag cgcactgtgg atggcgaagg ctacaacgta gcccaatgca 20520 acatgaccaa agactggttc ttggtacaga tgctcgccaa ctacaacatc ggctatcagg 20580 gcttctacat tccagaagga tacaaagatc gcatgtattc atttttcaga aacttccagc 20640 ccatgagcag gcaggtggtt gatgaggtca attacaaaga cttcaaggcc gtcgccatac 20700 cctaccaaca caacaactct ggctttgtgg gttacatggc tccgaccatg cgccaaggtc 20760 aaccctatcc cgctaactat ccctatccac tcattggaac aactgccgta aatagtgtta 20820 cgcagaaaaa gttcttgtgt gacagaacca tgtggcgcat accgttctcg agcaacttca 20880 tgtctatggg ggcccttaca gacttgggac agaatatgct ctatgccaac tcagctcatg 20940 ctctggacat gacctttgag gtggatccca tggatgagcc caccctgctt tatcttctct 21000 tcgaagtttt cgacgtggtc agagtgcatc agccacaccg cggcatcatc gaggcagtct 21060 acctgcgtac accgttctcg gccggtaacg ctaccacgta agaagcttct tgcttcttgc 21120 aaatagcagc tgcaaccatg gcctgcggat cccaaaacgg ctccagcgag caagagctca 21180 gagccattgt ccaagacctg ggttgcggac cctatttttt gggaacctac gataagcgct 21240 tcccggggtt catggccccc gataagctcg cctgtgccat tgtaaatacg gccggacgtg 21300 agacgggggg agagcactgg ttggctttcg gttggaaccc acgttctaac acctgctacc 21360 tttttgatcc ttttggattc tcggatgatc gtctcaaaca gatttaccag tttgaatatg 21420 agggtctcct gcgccgcagc gctcttgcta ccaaggaccg ctgtattacg ctggaaaaat 21480 ctacccagac cgtgcagggt ccccgttctg ccgcctgcgg acttttctgc tgcatgttcc 21540 ttcacgcctt tgtgcactgg cctgaccgtc ccatggacgg aaaccccacc atgaaattgc 21600 taactggagt gccaaacaac atgcttcatt ctcctaaagt ccagcccacc ctgtgtgaca 21660 atcaaaaagc actctaccat tttcttaata cccattcgcc ttattttcgc tcccatcgta 21720 cacacatcga aagggccact gcgttcgacc gtatggatgt tcaataatga ctcatgtaaa 21780 caacgtgttc aataaacatc actttatttt tttacatgta tcaaggctct gcattactta 21840 tttatttaca agtcgaatgg gttctgacga gaatcagaat gacccgcagg cagtgatacg 21900 ttgcggaact gatacttggg ttgccacttg aattcgggaa tcaccaactt gggaaccggt 21960 atatcgggca ggatgtcact ccacagcttt ctggtcagct gcaaagctcc aagcaggtca 22020 ggagccgaaa tcttgaaatc acaattagga ccagtgcttt gagcgcgaga gttgcggtac 22080 accggattgc agcactgaaa caccatcagc gacggatgtc tcacgcttgc cagcacggtg 22140 ggatctgcaa tcatgcccac atccagatct tcagcattgg caatgctgaa cggggtcatc 22200 ttgcaggtct gcctacccat ggcgggcacc caattaggct tgtggttgca atcgcagtgc 22260 agggggatca gtatcatctt ggcctgatcc tgtctgattc ctggatacac ggctctcatg 22320 aaagcatcat attgcttgaa agcctgctgg gctttactac cctcggtata aaacatcccg 22380 caggacctgc tcgaaaactg gttagctgca cagccggcat cattcacaca gcagcgggcg 22440 tcattgttag ctatttgcac cacacttctg ccccagcggt tttgggtgat tttggttcgc 22500 tcgggattct cctttaaggc tcgttgtccg ttctcgctgg ccacatccat ctcgataatc 22560 tgctccttct gaatcataat attgccatgc aggcacttca gcttgccctc ataatcattg 22620 cagccatgag gccacaacgc acagcctgta cattcccaat tatggtgggc gatctgagaa 22680 aaagaatgta tcattccctg cagaaatctt cccatcatcg tgctcagtgt cttgtgacta 22740 gtgaaagtta actggatgcc tcggtgctcc tcgtttacgt actggtgaca gatgcgcttg 22800 tattgttcgt gttgctcagg cattagttta aaagaggttc taagttcgtt atccagcctg 22860 tacttctcca tcagcagaca catcacttcc atgcctttct cccaagcaga caccaggggc 22920 aagctaatcg gattcttaac agtgcaggca gcagctcctt tagccagagg gtcatcttta 22980 gcgatcttct caatgcttct tttgccatcc ttctcaacga tgcgcacggg cgggtagctg 23040 aaacccactg ctacaagttg cgcctcttct ctttcttctt cgctgtcttg actgatgtct 23100 tgcatgggga tatgtttggt cttccttggc ttctttttgg ggggtatcgg aggaggagga 23160 ctgtcgctcc gttccggaga cagggaggat tgtgacgttt cgctcaccat taccaactga 23220 ctgtcggtag aagaacctga ccccacacgg cgacaggtgt ttctcttcgg gggcagaggt 23280 ggaggcgatt gcgaagggct gcggtccgac ctggaaggcg gatgactggc agaacccctt 23340 ccgcgttcgg gggtgtgctc cctgtggcgg tcgcttaact gatttccttc gcggctggcc 23400 attgtgttct cctaggcaga gaaacaacag acatggaaac tcagccattg ctgtcaacat 23460 cgccacgagt gccatcacat ctcgtcctca gcgacgagga aaaggagcag agcttaagca 23520 ttccaccgcc cagtcctgcc accacctcta ccctagaaga taaggaggtc gacgcatctc 23580 atgacatgca gaataaaaaa gcgaaagagt ctgagacaga catcgagcaa gacccgggct 23640 atgtgacacc ggtggaacac gaggaagagt tgaaacgctt tctagagaga gaggatgaaa 23700 actgcccaaa acaacgagca gataactatc accaagatgc tggaaatagg gatcagaaca 23760 ccgactacct catagggctt gacggggaag acgcgctcct taaacatcta gcaagacagt 23820 cgctcatagt caaggatgca ttattggaca gaactgaagt gcccatcagt gtggaagagc 23880 tcagccgcgc ctacgagctt aacctctttt cacctcgtac tccccccaaa cgtcagccaa 23940 acggcacctg cgagccaaat cctcgcttaa acttttatcc agcttttgct gtgccagaag 24000 tactggctac ctatcacatc ttttttaaaa atcaaaaaat tccagtctcc tgccgcgcta 24060 atcgcacccg cgccgatgcc ctactcaatc tgggacctgg ttcacgctta cctgatatag 24120 cttccttgga agaggttcca aagatcttcg agggtctggg caataatgag actcgggccg 24180 caaatgctct gcaaaaggga gaaaatggca tggatgagca tcacagcgtt ctggtggaat 24 240 tggaaggcga taatgccaga ctcgcagtac tcaagcgaag catcgaggtc acacacttcg 24300 catatcccgc tgtcaacctg ccccctaaag tcatgacggc ggtcatggac cagttactca 24360 ttaagcgcgc aagtcccctt tcagaagaca tgcatgaccc agatgcctgt gatgagggta 24420 aaccagtggt cagtgatgag cagctaaccc gatggctggg caccgactct cccagggatt 24480 tggaagagcg tcgcaagctt atgatggccg tggtgctggt taccgtagaa ctagagtgtc 24540 tccgacgttt ctttaccgat tcagaaacct tgcgcaaact cgaagagaat ctgcactaca 24600 cttttagaca cggctttgtg cggcaggcat gcaagatatc taacgtggaa ctcaccaacc 24660 tggtttccta catgggtatt ctgcatgaga atcgcctagg acaaagcgtg ctgcacagca 24720 ccctgaaggg ggaagcccgc cgtgattaca tccgcgattg tgtctatctg tacctgtgcc 24780 acacgtggca aaccggcatg ggtgtatggc agcaatgttt agaagaacag aacttgaaag 24840 agcttgacaa gctcttacag aaatctctta aggttctgtg gacagggttc gacgagcgca 24900 ccgtcgcttc cgacctggca gacctcatct tcccagagcg tctcagggtt actttgcgaa 24960 acggattgcc tgactttatg agccagagca tgcttaacaa ttttcgctct ttcatcctgg 25020 aacgctccgg tatcctgccc gccacctgct gcgcactgcc ctccgacttt gtgcctctca 25080 cctaccgcga gtgccccccg ccgctatgga gtcactgcta cctgttccgt ctggccaact 25 140 atctctccta ccactcggat gtgatcgagg atgtgagcgg agacggcttg ctggagtgtc 25200 actgccgctg caatctgtgc acgccccacc ggtccctagc ttgcaacccc cagttgatga 25260 gcgaaaccca gataataggc acctttgaat tgcaaggccc cagcagccaa ggcgatgggt 25320 cttctcctgg gcaaagttta aaactgaccc cgggactgtg gacctccgcc tacttgcgca 25380 agtttgctcc ggaagattac cacccctatg aaatcaagtt ctatgaggac caatcacagc 25440 ctccaaaggc cgaactttcg gcctgcgtca tcacccaggg ggcaattctg gcccaattgc 25500 aagccatcca aaaatcccgc caagaatttc tactgaaaaa gggtaagggg gtctaccttg 25560 acccccagac cggcgaggaa ctcaacacaa ggttccctca ggatgtccca acgacgagaa 25620 aacaagaagt tgaaggtgca gccgccgccc ccagaagata tggaggaaga ttgggacagt 25680 caggcagagg aggcggagga ggacagtctg gaggacagtc tggaggaaga cagtttggag 25740 gaggaaaacg aggaggcaga ggaggtggaa gaagtaaccg ccgacaaaca gttatcctcg 25800 gctgcggaga caagcaacag cgctaccatc tccgctccga gtcgaggaac ccggcggcgt 25860 cccagcagta gatgggacga gaccggacgc ttcccgaacc caaccagcgc ttccaagacc 25920 ggtaagaagg atcggcaggg atacaagtcc tggcgggggc ataagaatgc catcatctcc 25980 tgcttgcatg agtgcggggg caacatatcc ttcacgcggc gctacttgct attccaccat 26040 ggggtgaact ttccgcgcaa tgttttgcat tactaccgtc acctccacag cccctactat 26100 agccagcaaa tcccggcagt ctcgacagat aaagacagcg gcggcgacct ccaacagaaa 26160 accagcagcg gcagttagaa aatacacaac aagtgcagca acaggaggat taaagattac 26220 agccaacgag ccagcgcaaa cccgagagtt aagaaatcgg atctttccaa ccctgtatgc 26280 catcttccag cagagtcggg gtcaagagca ggaactgaaa ataaaaaacc gatctctgcg 26340 ttcgctcacc agaagttgtt tgtatcacaa gagcgaagat caacttcagc gcactctcga 26400 ggacgccgag gctctcttca acaagtactg cgcgctgact cttaaagagt aggcagcgac 26460 cgcgcttatt caaaaaaggc gggaattaca tcatcctcga catgagtaaa gaaattccca 26520 cgccttacat gtggagttat caaccccaaa tgggattggc ggcaggcgcc tcccaggact 26580 actccacccg catgaattgg ctcagcgccg ggccttctat gatttctcga gttaatgata 26640 tacgcgccta ccgaaaccaa atacttttgg aacagtcagc tcttaccacc acgccccgcc 26700 aacaccttaa tcccagaaat tggcccgccg ccctagtgta ccaggaaagt cccgctccca 26760 ccactgtatt acttcctcga gacgcccagg ccgaagtcca aatgactaat gcaggtgcgc 26820 agttagctgg cggctccacc ctatgtcgtc acaggcctcg gcataatata aaacgcctga 26880 tgatcagagg ccgaggtatc cagctcaacg acgagtcggt gagctctccg cttggtctac 26940 gaccagacgg aatctttcag attgccggct gcgggagatc ttccttcacc cctcgtcagg 27000 ctgttctgac tttggaaagt tcgtcttcgc aaccccgctc gggcggaatc gggaccgttc 27060 aatttgtgga ggagtttact ccctctgtct acttcaaccc cttctccgga tctcctgggc 27120 attacccgga cgagttcata ccgaacttcg acgcgattag cgagtcagtg gacggctacg 27180 attgatgtct ggtgacgcgg ctgagctatc tcggctgcga catctagacc actgccgccg 27240 ctttcgctgc tttgcccggg aactcattga gttcatctac ttcgaactcc ccaaggatca 27300 ccctcaaggt ccggcccacg gagtgcggat ttctatcgaa ggcaaaatag actctcgcct 27360 gcaacgaatt ttctcccagc ggcccgtgct gatcgagcga gaccagggaa acaccacggt 27420 ttccatctac tgcatttgta atcaccccgg attgcatgaa agcctttgct gtcttatgtg 27480 tactgagttt aataaaaact gaattaagac tctcctacgg actgccgctt cttcaacccg 27540 gattttacaa ccagaagaac gaaacttttc ctgtcgtcca ggactctgtt aacttcacct 27600 ttcctactca caaactagaa gctcaacgac tacaccgctt ttccagaagc attttcccta 27660 ctaatactac tttcaaaacc ggaggtgagc tccaaggtct tcctacagaa aacccttggg 27720 tggaagcggg ccttgtagtg ctaggaattc ttgcgggtgg gcttgtgatt attctttgct 27780 acctatacac accttgcttc actttcttag tggtgttgtg gtattggttt aaaaaatggg 27840 gcccatacta gtcttgcttg ttttactttc gcttttggaa ccgggttctg ccaattacga 27900 tccatgtcta gacttcgacc cagaaaactg cacacttact tttgcacccg acacaagccg 27960 catctgtgga gttcatcgcc tctcttacga acttggcccc caacgacaaa aatttacctg 28020 catggtggga atcaacccca tagttatcac ccagcaaagt ggagatacta agggttgcat 28080 tcactgctcc tgcgattcca tcgagtgcac ctacaccctg ctgaagaccc tatgcggcct 28140 aagagacctg ctaccaatga attaaaaaat gattaataaa aaatcactta cttgaaatca 28200 gcaataaggt ctctgttgaa attttctccc agcagcacct cacttccctc ttcccaactc 28260 tggtattcta aaccccgttc agcggcatac tttctccata ctttaaaggg gatgtcaaat 28320 tttagctcct ctcctgtacc cacaatcttc atgtctttct tcccagatga ccaagagagt 28380 ccggctcagt gactccttca accctgtcta cccctatgaa gatgaaagca cctcccaaca 28440 cccctttata aacccagggt ttatttcccc aaatggcttc acacaaagcc caaacggagt 28500 tcttacttta aaatgtttaa ccccactaac aaccacaggc ggatctctac agctaaaagt 28560 gggaggggga cttacagtgg atgacaccaa cggttttttg aaagaaaaca taagtgccac 28620 cacaccactc gttaagactg gtcactctat aggtttacca ctaggagccg gattgggaac 28680 gaatgaaaat aaactttgta tcaaattagg acaaggactt acattcaatt caaacaacat 28740 ttgcattgat gacaatatta acaccttatg gacaggagtc aaccccaccg aagccaactg 28800 tcaaatcatg aactccagtg aatctaatga ttgcaaatta attctaacac tagttaaaac 28860 tggagcacta gtcactgcat ttgtttatgt tataggagta tctaacaatt ttaatatgct 28920 aactacacac agaaatataa attttactgc agagctgttt ttcgattcta ctggtaattt 28980 actaactaga ctctcatccc tcaaaactcc acttaatcat aaatcaggac aaaacatggc 29040 tactggtgcc attactaatg ctaaaggttt catgcccagc acgactgcct atcctttcaa 29100 tgataattct agagaaaaag aaaactacat ttacggaact tgttactaca cagctagtga 29160 tcgcactgct tttcccattg acatatctgt catgcttaac cgaagagcaa taaatgacga 29220 gacatcatat tgtattcgta taacttggtc ctggaacaca ggagatgccc cagaggtgca 29280 aacctctgct acaaccctag tcacctcccc atttaccttt tactacatca gagaagacga 29340 ctgacaaata aagtttgcga tcgccaggcc accatggcct tgacctttgc tttactggtg 29400 gccctcctgg tgctcagctg caagtcaagc tgctctgtgg gctgtgatct gcctcaaacc 29460 cacagcctgg gtagcaggag gaccttgatg ctcctggcac agatgaggag aatctctctt 29520 ttctcctgct tgaaggacag acatgacttt ggatttcccc aggaggagtt tggcaaccag 29580 ttccaaaagg ctgaaaccat ccctgtcctc catgagatga tccagcagat cttcaatctc 29640 ttcagcacaa aggactcatc tgctgcttgg gatgagaccc tcctagacaa attctacact 29700 gaactctacc agcagctgaa tgacctggaa gcctgtgtga tacagggggt gggggtgaca 29760 gagactcccc tgatgaagga ggactccatt ctggctgtga ggaaatactt ccaaagaatc 29820 actctctatc tgaaagagaa gaaatacagc ccttgtgcct gggaggttgt cagagcagaa 29880 atcatgagat ctttttcttt gtcaacaaac ttgcaagaaa gtttaagaag taaggaagga 29940 agcggagcta ctaacttcag cctgctgaag caggctggag acgtggagga gaaccctgga 30000 cctcaggtct ccactgctgc ccttgccgtc ctcctctgca ccatggctct ctgcaaccag 30060 gtcctctctg caccacttgc tgctgacacg ccgaccgcct gctgcttcag ctacacctcc 30120 cgacagattc cacagaattt catagctgac tactttgaga cgagcagcca gtgctccaag 30180 cccagtgtca tcttcctaac caagagaggc cggcaggtct gtgctgaccc cagtgaggag 30240 tgggtccaga aatacgtcag tgacctggag ctgagtgccg gaagcggaga gggcagagga 30300 agtctgctaa catgcggtga cgtcgaggag aatcctggac ctggccacac acggaggcag 30360 ggaacatcac catccaagtg tccatacctc aatttctttc agctcttggt gctggctggt 30420 ctttctcact tctgttcagg tgttatccac gtgaccaagg aagtgaaaga agtggcaacg 30480 ctgtcctgtg gtcacaatgt ttctgttgaa gagctggcac aaactcgcat ctactggcaa 30540 aaggagaaga aaatggtgct gactatgatg tctggggaca tgaatatatg gcccgagtac 30600 aagaaccgga ccatctttga tatcactaat aacctctcca ttgtgatcct ggctctgcgc 30660 ccatctgacg agggcacata cgagtgtgtt gttctgaagt atgaaaaaga cgctttcaag 30720 cgggaacacc tggctgaagt gacgttatca gtcaaagctg acttccctac acctagtata 30780 tctgactttg aaattccaac ttctaatatt agaaggataa tttgctcaac ctctggaggt 30840 tttccagagc ctcacctctc ctggttggaa aatggagaag aattaaatgc catcaacaca 30900 acagtttccc aagatcctga aactgagctc tatgctgtta gcagcaaact ggatttcaat 30960 atgacaacca accacagctt catgtgtctc atcaagtatg gacatttaag agtgaatcag 31020 accttcaact ggaatacaac caagcaagag cattttcctg ataacctgct cccatcctgg 31080 gccattacct taatctcagt aaatggaatt tttgtgatat gctgcctgac ctactgcttt 31140 gccccaagat gcagagagag aaggaggaat gagagattga gaagggaaag tgtacgccct 31200 gtataagcta gcttgactga ctgagataca gcgtaccttc agctcacaga catgataaga 31260 tacattgatg agtttggaca aaccacaact agaatgcagt gaaaaaaatg ctttatttgt 31320 gaaatttgtg atgctattgc tttatttgta accattataa gctgcaataa acaagttaac 31380 aacaacaatt gcattcattt tatgtttcag gttcaggggg aggtgtggga ggttttttaa 31440 agcaagtaaa acctctacaa atgtggtagt cgtcagctat cctgcaggaa cttgtttatt 31500 tgaaaatcaa ttcacaaaat ccgagtagtt attttgcctc ccccttccca tttaacagaa 31560 tacaccaatc tctccccacg cacagcttta aacatttgga taccattaga tatagacatg 31620 gttttagatt ccacattcca aacagtttca gagcgagcca atctggggtc agtgatagat 31680 aaaaatccat cgggatagtc ttttaaagcg ctttcacagt ccaactgctg cggatgcgac 31740 tccggagtct ggatcacggt catctggaag aagaacgatg ggaatcataa tccgaaaacg 31800 gtatcggacg attgtgtctc atcaaaccca caagcagccg ctgtctgcgt cgctccgtgc 31860 gactgctgtt tatgggatca gggtccacag tgtcctgaag catgatttta atagccctta 31920 acatcaactt tctggtgcga tgcgcgcagc aacgcattct gatttcactc aaatctttgc 31980 agtaggtaca acacattatt acaatattgt ttaataaacc ataattaaaa gcgctccagc 32040 caaaactcat atctgatata atcgcccctg catgaccatc ataccaaagt ttaatataaa 32 100 ttaaatgacg ttccctcaaa aacacactac ccacatacat gatctctttt ggcatgtgca 32160 tattaacaat ctgtctgtac catggacaac gttggttaat catgcaaccc aatataacct 32220 tccggaacca cactgccaac accgctcccc cagccatgca ttgaagtgaa ccctgctgat 32280 tacaatgaca atgaagaacc caattctctc gaccgtgaat cacttgagaa tgaaaaatat 32340 ctatagtggc acaacataga cataaatgca tgcatcttct cataattttt aactcctcag 32400 gatttagaaa catatcccag ggaataggaa gctcttgcag aacagtaaag ctggcagaac 32460 aaggaagacc acgaacacaa cttacactat gcatagtcat agtatcacaa tctggcaaca 32520 gcgggtggtc ttcagtcata gaagctcggg tttcattttc ctcacaacgt ggtaactggg 32580 ctctggtgta agggtgatgt ctggcgcatg atgtcgagcg tgcgcgcaac cttgtcataa 32640 tggagttgct tcctgacatt ctcgtatttt gtatagcaaa acgcggccct ggcagaacac 32700 actcttcttc gccttctatc ctgccgctta gcgtgttccg tgtgatagtt caagtacaac 32760 cacactctta agttggtcaa aagaatgctg gcttcagttg taatcaaaac tccatcgcat 32820 ctaatcgttc tgaggaaatc atccaagcaa tgcaactgga ttgtgtttca agcaggagag 32880 gagagggaag agacggaaga accatgttaa tttttattcc aaacgatctc gcagtacttc 32940 aaattgtaga tcgcgcagat ggcatctctc gcccccactg tgttggtgaa aaagcacagc 33000 tagatcaaaa gaaatgcgat tttcaaggtg ctcaacggtg gcttccagca aagcctccac 33060 gcgcacatcc aagaacaaaa gaataccaaa agaaggagca ttttctaact cctcaatcat 33120 catattacat tcctgcacca ttcccagata attttcagct ttccagcctt gaattattcg 33180 tgtcagttct tgtggtaaat ccaatccaca cattacaaac aggtcccgga gggcgccctc 33 240 caccaccatt cttaaacaca ccctcataat gacaaaatat cttgctcctg tgtcacctgt 33300 agcgaattga gaatggcaac atcaattgac atgcccttgg ctctaagttc ttctttaagt 33360 tctagttgta aaaactctct catattatca ccaaactgct tagccagaag ccccccggga 33420 acaagagcag gggacgctac agtgcagtac aagcgcagac ctccccaatt ggctccagca 33480 aaaacaagat tggaataagc atattgggaa ccgccagtaa tatcatcgaa gttgctggaa 33540 atataatcag gcagagtttc ttgtaaaaat tgaataaaag aaaaatttgc caaaaaaaca 33600 ttcaaaacct ctgggatgca aatgcaatag gttaccgcgc tgcgctccaa cattgttagt 33660 tttgaattag tctgcaaaaa taaaaaaaaa aacaagcgtc atatcatagt agcctgacga 33720 acagatggat aaatcagtct ttccatcaca agacaagcca cagggtctcc agctcgaccc 33780 tcgtaaaacc tgtcatcatg attaaacaac agcaccgaaa gttcctcgcg gtgaccagca 33840 tgaataattc ttgatgaagc atacaatcca gacatgttag catcagttaa cgagaaaaaa 33900 cagccaacat agcctttggg tataattatg cttaatcgta agtatagcaa agccacccct 33960 cgcggataca aagtaaaagg cacaggagaa taaaaaatat aattatttct ctgctgctgt 34020 tcaggcaacg tcgcccccgg tccctctaaa tacacataca aagcctcatc agccatggct 34080 taccagacaa agtacagcgg gcacacaaag cacaagctct aaagtgactc tccaacctct 34 140 ccacaatata tatatacaca agccctaaac tgacgtaatg ggagtaaagt gtaaaaaatc 34200 ccgccaaacc caacacacac cccgaaactg cgtcaccagg gaaaagtaca gtttcacttc 34260 cgcaatccca acaggcgtaa cttcctcttt ctcacggtac gtgatatccc actaacttgc 34320 aacgtcattt tcccacggtc gcaccgcccc ttttagccgt taaccccaca gccaatcacc 34380 acacgatcca cactttttaa aatcacctca tttacatatt ggcaccattc catctataag 34440 gtatattata tagataga 34458 <210> 21 <211> 32326 <212> DNA <213> Artificial Sequence <220> <223> EnAd Genome <400> 21 tctatctata taatatacct tatagatgga atggtgccaa tatgtaaatg aggtgatttt 60 aaaaagtgtg gatcgtgtgg tgattggctg tggggttaac ggctaaaagg ggcggtgcga 120 ccgtgggaaa atgacgtttt gtgggggtgg agtttttttg caagttgtcg cgggaaatgt 180 gacgcataaa aaggcttttt tctcacggaa ctacttagtt ttcccacggt atttaacagg 240 aaatgaggta gttttgaccg gatgcaagtg aaaattgttg attttcgcgc gaaaactgaa 300 tgaggaagtg tttttctgaa taatgtggta tttatggcag ggtggagtat ttgttcaggg 360 ccaggtagac tttgacccat tacgtggagg tttcgattac cgtgtttttt acctgaattt 420 ccgcgtaccg tgtcaaagtc ttctgttttt acgtaggtgt cagctgatcg ctagggtatt 480 tatacctcag ggtttgtgtc aagaggccac tcttgagtgc cagcgagaag agttttctcc 540 tctgcgccgg cagtttaata ataaaaaaat gagagatttg cgatttctgc ctcaggaaat 600 aatctctgct gagactggaa atgaaatatt ggagcttgtg gtgcacgccc tgatgggaga 660 cgatccggag ccacctgtgc agctttttga gcctcctacg cttcaggaac tgtatgattt 720 agaggtagag ggatcggagg attctaatga ggaagctgta aatggctttt ttaccgattc 780 tatgctttta gctgctaatg aagggttaga attagatccg cctttggaca cttttgatac 840 tccaggggta attgtggaaa gcggtacagg tgtaagaaaa ttacctgatt tgagttccgt 900 ggactgtgat ttgcactgct atgaagacgg gtttcctccg agtgatgagg aggaccatga 960 aaaggagcag tccatgcaga ctgcagcggg tgagggagtg aaggctgcca atgttggttt 1020 tcagttggat tgcccggagc ttcctggaca tggctgtaag tcttgtgaat ttcacaggaa 1080 aaatactgga gtaaaggaac tgttatgttc gctttgttat atgagaacgc actgccactt 1140 tatttacagt aagtgtgttt aagttaaaat ttaaaggaat atgctgtttt tcacatgtat 1200 attgagtgtg agttttgtgc ttcttattat aggtcctgtg tctgatgctg atgaatcacc 1260 atctcctgat tctactacct cacctcctga gattcaagca cctgttcctg tggacgtgcg 1320 caagcccatt cctgtgaagc ttaagcctgg gaaacgtcca gcagtggaaa aacttgagga 1380 cttgttacag ggtggggacg gacctttgga cttgagtaca cggaaacgtc caagacaata 1440 agtgttccat atccgtgttt acttaaggtg acgtcaatat ttgtgtgaca gtgcaatgta 1500 ataaaaatat gttaactgtt cactggtttt tattgctttt tgggcgggga ctcaggtata 1560 taagtagaag cagacctgtg tggttagctc ataggagctg gctttcatcc atggaggttt 1620 gggccatttt ggaagacctt aggaagacta ggcaactgtt agagaacgct tcggacggag 1680 tctccggttt ttggagattc tggttcgcta gtgaattagc tagggtagtt tttaggataa 1740 aacaggacta taaacaagaa tttgaaaagt tgttggtaga ttgcccagga ctttttgaag 1800 ctcttaattt gggccatcag gttcacttta aagaaaaagt tttatcagtt ttagactttt 1860 caaccccagg tagaactgct gctgctgtgg cttttcttac ttttatatta gataaatgga 1920 tcccgcagac tcatttcagc aggggatacg ttttggattt catagccaca gcattgtgga 1980 gaacatggaa ggttcgcaag atgaggacaa tcttaggtta ctggccagtg cagcctttgg 2040 gtgtagcggg aatcctgagg catccaccgg tcatgccagc ggttctggag gaggaacagc 2100 aagaggacaa cccgagagcc ggcctggacc ctccagtgga ggaggcggag tagctgactt 2160 gtctcctgaa ctgcaacggg tgcttactgg atctacgtcc actggacggg ataggggcgt 2220 taagagggag agggcatcta gtggtactga tgctagatct gagttggctt taagtttaat 2280 gagtcgcaga cgtcctgaaa ccatttggtg gcatgaggtt cagaaagagg gaagggatga 2340 agtttctgta ttgcaggaga aatattcact ggaacaggtg aaaacatgtt ggttggagcc 2400 tgaggatgat tgggaggtgg ccattaaaaa ttatgccaag atagctttga ggcctgataa 2460 acagtataag attactagac ggattaatat ccggaatgct tgttacatat ctggaaatgg 2520 ggctgaggtg gtaatagata ctcaagacaa ggcagttatt agatgctgca tgatggatat 2580 gtggcctggg gtagtcggta tggaagcagt aacttttgta aatgttaagt ttaggggaga 2640 tggttataat ggaatagtgt ttatggccaa taccaaactt atattgcatg gttgtagctt 2700 ttttggtttc aacaatacct gtgtagatgc ctggggacag gttagtgtac ggggatgtag 2760 tttctatgcg tgttggattg ccacagctgg cagaaccaag agtcaattgt ctctgaagaa 2820 atgcatattt caaagatgta acctgggcat tctgaatgaa ggcgaagcaa gggtccgcca 2880 ctgcgcttct acagatactg gatgttttat tttgattaag ggaaatgcca gcgtaaagca 2940 taacatgatt tgcggtgctt ccgatgagag gccttatcaa atgctcactt gtgctggtgg 3000 gcattgtaat atgctggcta ctgtgcatat tgtttcccat caacgcaaaa aatggcctgt 3060 ttttgatcac aatgtgatga cgaagtgtac catgcatgca ggtgggcgta gaggaatgtt 3120 tatgccttac cagtgtaaca tgaatcatgt gaaagtgttg ttggaaccag atgccttttc 3180 cagaatgagc ctaacaggaa tttttgacat gaacatgcaa atctggaaga tcctgaggta 3240 tgatgatacg agatcgaggg tacgcgcatg cgaatgcgga ggcaagcatg ccaggttcca 3300 gccggtgtgt gtagatgtga ctgaagatct cagaccggat catttggtta ttgcccgcac 3360 tggagcagag ttcggatcca gtggagaaga aactgactaa ggtgagtatt gggaaaactt 3420 tggggtggga ttttcagatg gacagattga gtaaaaattt gttttttctg tcttgcagct 3480 gtcatgagtg gaaacgcttc ttttaagggg ggagtcttca gcccttatct gacagggcgt 3540 ctcccatcct gggcaggagt tcgtcagaat gttatgggat ctactgtgga tggaagaccc 3600 gtccaacccg ccaattcttc aacgctgacc tatgctactt taagttcttc acctttggac 3660 gcagctgcag ctgccgccgc cgcttctgtt gccgctaaca ctgtgcttgg aatgggttac 3720 tatggaagca tcatggctaa ttccacttcc tctaataacc cttctaccct gactcaggac 3780 aagttacttg tccttttggc ccagctggag gctttgaccc aacgtctggg tgaactttct 3840 cagcaggtgg tcgagttgcg agtacaaact gagtctgctg tcggcacggc aaagtctaaa 3900 taaaaaaatc ccagaatcaa tgaataaata aacaagcttg ttgttgattt aaaatcaagt 3960 gtttttattt catttttcgc gcacggtatg ccctagacca ccgatctcta tcattgagaa 4020 ctcggtggat tttttccagg atcctataga ggtgggattg aatgtttaga tacatgggca 4080 ttaggccgtc tttggggtgg agatagctcc attgaaggga ttcatgctcc ggggtagtgt 4140 tgtaaatcac ccagtcataa caaggtcgca gtgcatggtg ttgcacaata tcttttagaa 4200 gtaggctgat tgccacagat aagcccttgg tgtaggtgtt tacaaaccgg ttgagctggg 4260 atgggtgcat tcggggtgaa attatgtgca ttttggattg gatttttaag ttggcaatat 4320 tgccgccaag atcccgtctt gggttcatgt tatgaaggac caccaagacg gtgtatccgg 4380 tacatttagg aaatttatcg tgcagcttgg atggaaaagc gtggaaaaat ttggagacac 4440 ccttgtgtcc tccaagattt tccatgcact catccatgat aatagcaatg gggccgtggg 4500 cagcggcgcg ggcaaacacg ttccgtgggt ctgacacatc atagttatgt tcctgagtta 4560 aatcatcata agccatttta atgaatttgg ggcggagagt accagattgg ggtatgaatg 4620 ttccttcggg ccccggagca tagttcccct cacagatttg catttcccaa gctttcagtt 4680 ccgagggtgg aatcatgtcc acctgggggg ctatgaaaaa caccgtttct ggggcggggg 4740 tgattaattg tgatgatagc aaatttctga gcaattgaga tttgccacat ccggtggggc 4800 cataaatgat tccgattacg ggttgcaggt ggtagtttag ggaacggcaa ctgccgtctt 4860 ctcgaagcaa gggggccacc tcgttcatca tttcccttac atgcatattt tcccgcacca 4920 aatccattag gaggcgctct cctcctagtg atagaagttc ttgtagtgag gaaaagtttt 4980 tcagcggttt cagaccgtca gccatgggca ttttggagag agtttgctgc aaaagttcta 5040 gtctgttcca cagttcagtg atgtgttcta tggcatctcg atccagcaga cctcctcgtt 5100 tcgcgggttt ggacggctcc tggaataggg tatgagacga tgggcgtcca gcgctgccag 5160 ggttcggtcc ttccagggtc tcagtgttcg agtcagggtt gtttccgtca cagtgaaggg 5220 gtgtgcgcct gcttgggcgc ttgccagggt gcgcttcaga ctcatcctgc tggtcgaaaa 5280 cttctgtcgc ttggcgccct gtatgtcggc caagtagcag tttaccatga gttcgtagtt 5340 gagcgcctcg gctgcgtggc ctttggcgcg gagcttacct ttggaagttt tcttgcatac 5400 cgggcagtat aggcatttca gcgcatacaa cttgggcgca aggaaaacgg attctgggga 5460 gtatgcatct gcgccgcagg aggcgcaaac agtttcacat tccaccagcc aggttaaatc 5520 cggttcattg gggtcaaaaa caagttttcc gccatatttt ttgatgcgtt tcttaccttt 5580 ggtctccatg agttcgtgtc ctcgttgagt gacaaacagg ctgtccgtgt ccccgtagac 5640 tgattttaca ggcctcttct ccagtggagt gcctcggtct tcttcgtaca ggaactctga 5700 ccactctgat acaaaggcgc gcgtccaggc cagcacaaag gaggctatgt gggaggggta 5760 gcgatcgttg tcaaccaggg ggtccacctt ttccaaagta tgcaaacaca tgtcaccctc 5820 ttcaacatcc aggaatgtga ttggcttgta ggtgtatttc acgtgacctg gggtccccgc 5880 tgggggggta taaaaggggg cggttctttg ctcttcctca ctgtcttccg gatcgctgtc 5940 caggaacgtc agctgttggg gtaggtattc cctctcgaag gcgggcatga cctctgcact 6000 caggttgtca gtttctaaga acgaggagga tttgatattg acagtgccgg ttgagatgcc 6060 tttcatgagg ttttcgtcca tctggtcaga aaacacaatt tttttattgt caagtttggt 6120 ggcaaatgat ccatacaggg cgttggataa aagtttggca atggatcgca tggtttggtt 6180 cttttccttg tccgcgcgct ctttggcggc gatgttgagt tggacatact cgcgtgccag 6240 gcacttccat tcggggaaga tagttgttaa ttcatctggc acgattctca cttgccaccc 6300 tcgattatgc aaggtaatta aatccacact ggtggccacc tcgcctcgaa ggggttcatt 6360 ggtccaacag agcctacctc ctttcctaga acagaaaggg ggaagtgggt ctagcataag 6420 ttcatcggga gggtctgcat ccatggtaaa gattcccgga agtaaatcct tatcaaaata 6480 gctgatggga gtggggtcat ctaaggccat ttgccattct cgagctgcca gtgcgcgctc 6540 atatgggtta aggggactgc cccatggcat gggatgggtg agtgcagagg catacatgcc 6600 acagatgtca tagacgtaga tgggatcctc aaagatgcct atgtaggttg gatagcatcg 6660 cccccctctg atacttgctc gcacatagtc atatagttca tgtgatggcg ctagcagccc 6720 cggacccaag ttggtgcgat tgggtttttc tgttctgtag acgatctggc gaaagatggc 6780 gtgagaattg gaagagatgg tgggtctttg aaaaatgttg aaatgggcat gaggtagacc 6840 tacagagtct ctgacaaagt gggcataaga ttcttgaagc ttggttacca gttcggcggt 6900 gacaagtacg tctagggcgc agtagtcaag tgtttcttga atgatgtcat aacctggttg 6960 gtttttcttt tcccacagtt cgcggttgag aaggtattct tcgcgatcct tccagtactc 7020 ttctagcgga aacccgtctt tgtctgcacg gtaagatcct agcatgtaga actgattaac 7080 tgccttgtaa gggcagcagc ccttctctac gggtagagag tatgcttgag cagcttttcg 7140 tagcgaagcg tgagtaaggg caaaggtgtc tctgaccatg actttgagga attggtattt 7200 gaagtcgatg tcgtcacagg ctccctgttc ccagagttgg aagtctaccc gtttcttgta 7260 ggcggggttg ggcaaagcga aagtaacatc attgaagaga atcttgccgg ccctgggcat 7320 gaaattgcga gtgatgcgaa aaggctgtgg tacttccgct cggttattga taacctgggc 7380 agctaggacg atctcgtcga aaccgttgat gttgtgtcct acgatgtata attctatgaa 7440 acgcggcgtg cctctgacgt gaggtagctt actgagctca tcaaaggtta ggtctgtggg 7500 gtcagataag gcgtagtgtt cgagagccca ttcgtgcagg tgaggattcg ctttaaggaa 7560 ggaggaccag aggtccactg ccagtgctgt ttgtaactgg tcccggtact gacgaaaatg 7620 ccgtccgact gccatttttt ctggggtgac gcaatagaag gtttgggggt cctgccgcca 7680 gcgatcccac ttgagtttta tggcgaggtc ataggcgatg ttgacgagcc gctggtctcc 7740 agagagtttc atgaccagca tgaaggggat tagctgcttg ccaaaggacc ccatccaggt 7800 gtaggtttcc acatcgtagg tgagaaagag cctttctgtg cgaggatgag agccaatcgg 7860 gaagaactgg atctcctgcc accagttgga ggaatggctg ttgatgtgat ggaagtagaa 7920 ctccctgcga cgcgccgagc attcatgctt gtgcttgtac agacggccgc agtagtcgca 7980 gcgttgcacg ggttgtatct cgtgaatgag ttgtacctgg cttcccttga cgagaaattt 8040 cagtgggaag ccgaggcctg gcgattgtat ctcgtgcttt actatgttgt ctgcatcggc 8100 ctgttcatct tctgtctcga tggtggtcat gctgacgagc cctcgcggga ggcaagtcca 8160 gacctcggcg cggcaggggc ggagctcgag gacgagagcg cgcaggctgg agctgtccag 8220 ggtcctgaga cgctgcggac tcaggttagt aggcagtgtc aggagattaa cttgcatgat 8280 cttttggagg gcgtgcggga ggttcagata gtacttgatc tcaacgggtc cgttggtgga 8340 gatgtcgatg gcttgcaggg ttccgtgtcc cttgggcgct accaccgtgc ccttgttttt 8400 cattttggac ggcggtggct ctgttgcttc ttgcatgttt agaagcggtg tcgagggcgc 8460 gcaccgggcg gcaggggcgg ctcgggaccc ggcggcatgg ctggcagtgg tacgtcggcg 8520 ccgcgcgcgg gtaggttctg gtactgcgcc ctgagaagac tcgcatgcgc gacgacgcgg 8580 cggttgacat cctggatctg acgcctctgg gtgaaagcta ccggccccgt gagcttgaac 8640 ctgaaagaga gttcaacaga atcaatctcg gtatcgttga cggcggcttg cctaaggatt 8700 tcttgcacgt caccagagtt gtcctggtag gcgatctccg ccatgaactg ctcgatctct 8760 tcctcttgaa gatctccgcg gcccgctctc tcgacggtgg ccgcgaggtc gttggagatg 8820 cgcccaatga gttgagagaa tgcattcatg cccgcctcgt tccagacgcg gctgtagacc 8880 acggccccca cgggatctct cgcgcgcatg accacctggg cgaggttgag ctccacgtgg 8940 cgggtgaaga ccgcatagtt gcataggcgc tggaaaaggt agttgagtgt ggtggcgatg 9000 tgctcggtga cgaagaaata catgatccat cgtctcagcg gcatctcgct gacatcgccc 9060 agagcttcca agcgctccat ggcctcgtag aagtccacgg caaaattaaa aaactgggag 9120 tttcgcgcgg acacggtcaa ctcctcttcc agaagacgga taagttcggc gatggtggtg 9180 cgcacctcgc gctcgaaagc ccctgggatt tcttcctcaa tctcttcttc ttccactaac 9240 atctcttcct cttcaggtgg ggctgcagga ggagggggaa cgcggcgacg ccggcggcgc 9300 acgggcagac ggtcgatgaa tctttcaatg acctctccgc ggcggcggcg catggtttca 9360 gtgacggcgc ggccgttctc gcgcggtcgc agagtaaaaa caccgccgcg catctcctta 9420 aagtggtgac tgggaggttc tccgtttggg agggagaggg cgctgattat acattttatt 9480 aattggcccg tagggactgc acgcagagat ctgatcgtgt caagatccac gggatctgaa 9540 aacctttcga cgaaagcgtc taaccagtca cagtcacaag gtaggctgag tacggcttct 9600 tgtgggcggg ggtggttatg tgttcggtct gggtcttctg tttcttcttc atctcgggaa 9660 ggtgagacga tgctgctggt gatgaaatta aagtaggcag ttctaagacg gcggatggtg 9720 gcgaggagca ccaggtcttt gggtccggct tgctggatac gcaggcgatt ggccattccc 9780 caagcattat cctgacatct agcaagatct ttgtagtagt cttgcatgag ccgttctacg 9840 ggcacttctt cctcacccgt tctgccatgc atacgtgtga gtccaaatcc gcgcattggt 9900 tgtaccagtg ccaagtcagc tacgactctt tcggcgagga tggcttgctg tacttgggta 9960 agggtggctt gaaagtcatc aaaatccaca aagcggtggt aagctcctgt attaatggtg 10020 taagcacagt tggccatgac tgaccagtta actgtctggt gaccagggcg cacgagctcg 10080 gtgtatttaa ggcgcgaata ggcgcgggtg tcaaagatgt aatcgttgca ggtgcgcacc 10140 agatactggt accctataag aaaatgcggc ggtggttggc ggtagagagg ccatcgttct 10200 gtagctggag cgccaggggc gaggtcttcc aacataaggc ggtgatagcc gtagatgtac 10260 ctggacatcc aggtgattcc tgcggcggta gtagaagccc gaggaaactc gcgtacgcgg 10320 ttccaaatgt tgcgtagcgg catgaagtag ttcattgtag gcacggtttg accagtgagg 10380 cgcgcgcagt cattgatgct ctatagacac ggagaaaatg aaagcgttca gcgactcgac 10440 tccgtagcct ggaggaacgt gaacgggttg ggtcgcggtg taccccggtt cgagacttgt 10500 actcgagccg gccggagccg cggctaacgt ggtattggca ctcccgtctc gacccagcct 10560 acaaaaatcc aggatacgga atcgagtcgt tttgctggtt tccgaatggc agggaagtga 10620 gtcctatttt ttttttttgc cgctcagatg catcccgtgc tgcgacagat gcgcccccaa 10680 caacagcccc cctcgcagca gcagcagcag caatcacaaa aggctgtccc tgcaactact 10740 gcaactgccg ccgtgagcgg tgcgggacag cccgcctatg atctggactt ggaagagggc 10800 gaaggactgg cacgtctagg tgcgccttca cccgagcggc atccgcgagt tcaactgaaa 10860 aaagattctc gcgaggcgta tgtgccccaa cagaacctat ttagagacag aagcggcgag 10920 gagccggagg agatgcgagc ttcccgcttt aacgcgggtc gtgagctgcg tcacggtttg 10980 gaccgaagac gagtgttgcg ggacgaggat ttcgaagttg atgaaatgac agggatcagt 11040 cctgccaggg cacacgtggc tgcagccaac cttgtatcgg cttacgagca gacagtaaag 11 100 gaagagcgta acttccaaaa gtcttttaat aatcatgtgc gaaccctgat tgcccgcgaa 11160 gaagttaccc ttggtttgat gcatttgtgg gatttgatgg aagctatcat tcagaaccct 11220 actagcaaac ctctgaccgc ccagctgttt ctggtggtgc aacacagcag agacaatgag 11280 gctttcagag aggcgctgct gaacatcacc gaacccgagg ggagatggtt gtatgatctt 11340 atcaacattc tacagagtat catagtgcag gagcggagcc tgggcctggc cgagaaggtg 11400 gctgccatca attactcggt tttgagcttg ggaaaatatt acgctcgcaa aatctacaag 11460 actccatacg ttcccataga caaggaggtg aagatagatg ggttctacat gcgcatgacg 11520 ctcaaggtct tgaccctgag cgatgatctt ggggtgtatc gcaatgacag aatgcatcgc 11580 gcggttagcg ccagcaggag gcgcgagtta agcgacaggg aactgatgca cagtttgcaa 11640 agagctctga ctggagctgg aaccgagggt gagaattact tcgacatggg agctgacttg 11700 cagtggcagc ctagtcgcag ggctctgagc gccgcgacgg caggatgtga gcttccttac 11760 atagaagagg cggatgaagg cgaggaggaa gagggcgagt acttggaaga ctgatggcac 11820 aacccgtgtt ttttgctaga tggaacagca agcaccggat cccgcaatgc gggcggcgct 11880 gcagagccag ccgtccggca ttaactcctc ggacgattgg acccaggcca tgcaacgtat 11940 catggcgttg acgactcgca accccgaagc ctttagacag caaccccagg ccaaccgtct 12000 atcggccatc atggaagctg tagtgccttc ccgctctaat cccactcatg agaaggtcct 12060 ggccatcgtg aacgcgttgg tggagaacaa agctattcgt ccagatgagg ccggactggt 12120 atacaacgct ctcttagaac gcgtggctcg ctacaacagt agcaatgtgc aaaccaattt 12180 ggaccgtatg ataacagatg tacgcgaagc cgtgtctcag cgcgaaaggt tccagcgtga 12240 tgccaacctg ggttcgctgg tggcgttaaa tgctttcttg agtactcagc ctgctaatgt 12300 gccgcgtggt caacaggatt atactaactt tttaagtgct ttgagactga tggtatcaga 12360 agtacctcag agcgaagtgt atcagtccgg tcctgattac ttctttcaga ctagcagaca 12420 gggcttgcag acggtaaatc tgagccaagc ttttaaaaac cttaaaggtt tgtggggagt 12480 gcatgccccg gtaggagaaa gagcaaccgt gtctagcttg ttaactccga actcccgcct 12540 attattactg ttggtagctc ctttcaccga cagcggtagc atcgaccgta attcctattt 12600 gggttaccta ctaaacctgt atcgcgaagc catagggcaa agtcaggtgg acgagcagac 12660 ctatcaagaa attacccaag tcagtcgcgc tttgggacag gaagacactg gcagtttgga 12720 agccactctg aacttcttgc ttaccaatcg gtctcaaaag atccctcctc aatatgctct 12780 tactgcggag gaggagagga tccttagata tgtgcagcag agcgtgggat tgtttctgat 12840 gcaagagggg gcaactccga ctgcagcact ggacatgaca gcgcgaaata tggagcccag 12900 catgtatgcc agtaaccgac ctttcattaa caaactgctg gactacttgc acagagctgc 12960 cgctatgaac tctgattatt tcaccaatgc catcttaaac ccgcactggc tgcccccacc 13020 tggtttctac acgggcgaat atgacatgcc cgaccctaat gacggatttc tgtgggacga 13080 cgtggacagc gatgtttttt cacctctttc tgatcatcgc acgtggaaaa aggaaggcgg 13140 cgatagaatg cattcttctg catcgctgtc cggggtcatg ggtgctaccg cggctgagcc 13200 cgagtctgca agtccttttc ctagtctacc cttttctcta cacagtgtac gtagcagcga 13260 agtgggtaga ataagtcgcc cgagtttaat gggcgaagag gagtatctaa acgattcctt 13320 gctcagaccg gcaagagaaa aaaatttccc aaacaatgga atagaaagtt tggtggataa 13380 aatgagtaga tggaagactt atgctcagga tcacagagac gagcctggga tcatggggat 13440 tacaagtaga gcgagccgta gacgccagcg ccatgacaga cagaggggtc ttgtgtggga 13500 cgatgaggat tcggccgatg atagcagcgt gctggacttg ggtgggagag gaaggggcaa 13560 cccgtttgct catttgcgcc ctcgcttggg tggtatgttg taaaaaaaaa taaaaaaaaa 13620 actcaccaag gccatggcga cgagcgtacg ttcgttcttc tttattatct gtgtctagta 13680 taatgaggcg agtcgtgcta ggcggagcgg tggtgtatcc ggagggtcct cctccttcgt 13740 acgagagcgt gatgcagcag cagcaggcga cggcggtgat gcaatcccca ctggaggctc 13800 cctttgtgcc tccgcgatac ctggcaccta cggagggcag aaacagcatt cgttattcgg 13860 aactggcacc tcagtacgat accaccaggt tgtatctggt ggacaacaag tcggcggaca 13920 ttgcttctct gaactatcag aatgaccaca gcaacttctt gaccacggtg gtgcaaaaca 13980 atgactttac ccctacggaa gccagcaccc agaccattaa ctttgatgaa cgatcgcggt 14040 ggggcggtca gctaaagacc atcatgcata ctaacatgcc aaacgtgaac gagtatatgt 14100 ttagtaacaa gttcaaagcg cgtgtgatgg tgtccagaaa acctcccgac ggtgctgcag 14160 ttggggatac ttatgatcac aagcaggata ttttgaaata tgagtggttc gagtttactt 14220 tgccagaagg caacttttca gttactatga ctattgattt gatgaacaat gccatcatag 14280 ataattactt gaaagtgggt agacagaatg gagtgcttga aagtgacatt ggtgttaagt 14340 tcgacaccag gaacttcaag ctgggatggg atcccgaaac caagttgatc atgcctggag 14400 tgtatacgta tgaagccttc catcctgaca ttgtcttact gcctggctgc ggagtggatt 14460 ttaccgagag tcgtttgagc aaccttcttg gtatcagaaa aaaacagcca tttcaagagg 14520 gttttaagat tttgtatgaa gatttagaag gtggtaatat tccggccctc ttggatgtag 14580 atgcctatga gaacagtaag aaagaacaaa aagccaaaat agaagctgct acagctgctg 14640 cagaagctaa ggcaaacata gttgccagcg actctacaag ggttgctaac gctggagagg 14700 tcagaggaga caattttgcg ccaacacctg ttccgactgc agaatcatta ttggccgatg 14760 tgtctgaagg aacggacgtg aaactcacta ttcaacctgt agaaaaagat agtaagaata 14820 gaagctataa tgtgttggaa gacaaaatca acacagccta tcgcagttgg tatctttcgt 14880 acaattatgg cgatcccgaa aaaggagtgc gttcctggac attgctcacc acctcagatg 14940 tcacctgcgg agcagagcag gtctactggt cgcttccaga catgatgaag gatcctgtca 15000 ctttccgctc cactagacaa gtcagtaact accctgtggt gggtgcagag cttatgcccg 15060 tcttctcaaa gagcttctac aacgaacaag ctgtgtactc ccagcagctc cgccagtcca 15120 cctcgcttac gcacgtcttc aaccgctttc ctgagaacca gattttaatc cgtccgccgg 15180 cgcccaccat taccaccgtc agtgaaaacg ttcctgctct cacagatcac gggaccctgc 15240 cgttgcgcag cagtatccgg ggagtccaac gtgtgaccgt tactgacgcc agacgccgca 15300 cctgtcccta cgtgtacaag gcactgggca tagtcgcacc gcgcgtcctt tcaagccgca 15360 ctttctaaaa aaaaaaaaaa tgtccattct tatctcgccc agtaataaca ccggttgggg 15420 tctgcgcgct ccaagcaaga tgtacggagg cgcacgcaaa cgttctaccc aacatcctgt 15480 ccgtgttcgc ggacattttc gcgctccatg gggcgccctc aagggccgca ctcgcgttcg 15540 aaccaccgtc gatgatgtaa tcgatcaggt ggttgccgac gcccgtaatt atactcctac 15600 tgcgcctaca tctactgtgg atgcagttat tgacagtgta gtggctgacg ctcgcaacta 15660 tgctcgacgt aagagccggc gaaggcgcat tgccagacgc caccgagcta ccactgccat 15720 gcgagccgca agagctctgc tacgaagagc tagacgcgtg gggcgaagag ccatgcttag 15780 ggcggccaga cgtgcagctt cgggcgccag cgccggcagg tcccgcaggc aagcagccgc 15840 tgtcgcagcg gcgactattg ccgacatggc ccaatcgcga agaggcaatg tatactgggt 15900 gcgtgacgct gccaccggtc aacgtgtacc cgtgcgcacc cgtccccctc gcacttagaa 15960 gatactgagc agtctccgat gttgtgtccc agcggcgagg atgtccaagc gcaaatacaa 16020 ggaagaaatg ctgcaggtta tcgcacctga agtctacggc caaccgttga aggatgaaaa 16080 aaaaccccgc aaaatcaagc gggttaaaaa ggacaaaaaa gaagaggaag atggcgatga 16140 tgggctggcg gagtttgtgc gcgagtttgc cccacggcga cgcgtgcaat ggcgtgggcg 16200 caaagttcga catgtgttga gacctggaac ttcggtggtc tttacacccg gcgagcgttc 16260 aagcgctact tttaagcgtt cctatgatga ggtgtacggg gatgatgata ttcttgagca 16320 ggcggctgac cgattaggcg agtttgctta tggcaagcgt agtagaataa cttccaagga 16380 tgagacagtg tcgataccct tggatcatgg aaatcccacc cctagtctta aaccggtcac 16440 tttgcagcaa gtgttacccg taactccgcg aacaggtgtt aaacgcgaag gtgaagattt 16500 gtatcccact atgcaactga tggtacccaa acgccagaag ttggaggacg ttttggagaa 16560 agtaaaagtg gatccagata ttcaacctga ggttaaagtg agacccatta agcaggtagc 16620 gcctggtctg ggggtacaaa ctgtagacat taagattccc actgaaagta tggaagtgca 16680 aactgaaccc gcaaagccta ctgccacctc cactgaagtg caaacggatc catggatgcc 16740 catgcctatt acaactgacg ccgccggtcc cactcgaaga tcccgacgaa agtacggtcc 16800 agcaagtctg ttgatgccca attatgttgt acacccatct attattccta ctcctggtta 16860 ccgaggcact cgctactatc gcagccgaaa cagtacctcc cgccgtcgcc gcaagacacc 16920 tgcaaatcgc agtcgtcgcc gtagacgcac aagcaaaccg actcccggcg ccctggtgcg 16980 gcaagtgtac cgcaatggta gtgcggaacc tttgacactg ccgcgtgcgc gttaccatcc 17040 gagtatcatc acttaatcaa tgttgccgct gcctccttgc agatatggcc ctcacttgtc 17100 gccttcgcgt tcccatcact ggttaccgag gaagaaactc gcgccgtaga agagggatgt 17160 tgggacgcgg aatgcgacgc tacaggcgac ggcgtgctat ccgcaagcaa ttgcggggtg 17220 gttttttacc agccttaatt ccaattatcg ctgctgcaat tggcgcgata ccaggcatag 17280 cttccgtggc ggttcaggcc tcgcaacgac attgacattg gaaaaaaacg tataaataaa 17340 aaaaaaaaaa tacaatggac tctgacactc ctggtcctgt gactatgttt tcttagagat 17400 ggaagacatc aatttttcat ccttggctcc gcgacacggc acgaagccgt acatgggcac 17460 ctggagcgac atcggcacga gccaactgaa cgggggcgcc ttcaattgga gcagtatctg 17520 gagcgggctt aaaaattttg gctcaaccat aaaaacatac gggaacaaag cttggaacag 17580 cagtacagga caggcgctta gaaataaact taaagaccag aacttccaac aaaaagtagt 17640 cgatgggata gcttccggca tcaatggagt ggtagatttg gctaaccagg ctgtgcagaa 17700 aaagataaac agtcgtttgg acccgccgcc agcaacccca ggtgaaatgc aagtggagga 17760 agaaattcct ccgccagaaa aacgaggcga caagcgtccg cgtcccgatt tggaagagac 17820 gctggtgacg cgcgtagatg aaccgccttc ttatgaggaa gcaacgaagc ttggaatgcc 17880 caccactaga ccgatagccc caatggccac cggggtgatg aaaccttctc agttgcatcg 17940 acccgtcacc ttggatttgc cccctccccc tgctgctact gctgtacccg cttctaagcc 18000 tgtcgctgcc ccgaaaccag tcgccgtagc caggtcacgt cccgggggcg ctcctcgtcc 18060 aaatgcgcac tggcaaaata ctctgaacag catcgtgggt ctaggcgtgc aaagtgtaaa 18 120 acgccgtcgc tgcttttaat taaatatgga gtagcgctta acttgcctat ctgtgtatat 18180 gtgtcattac acgccgtcac agcagcagag gaaaaaagga agaggtcgtg cgtcgacgct 18240 gagttacttt caagatggcc accccatcga tgctgcccca atgggcatac atgcacatcg 18300 ccggacagga tgcttcggag tacctgagtc cgggtctggt gcagttcgcc cgcgccacag 18360 acacctactt caatctggga aataagttta gaaatcccac cgtagcgccg acccacgatg 18420 tgaccaccga ccgtagccag cggctcatgt tgcgcttcgt gcccgttgac cgggaggaca 18480 atacatactc ttacaaagtg cggtacaccc tggccgtggg cgacaacaga gtgctggata 18540 tggccagcac gttctttgac attaggggtg tgttggacag aggtcccagt ttcaaaccct 18600 attctggtac ggcttacaac tccctggctc ctaaaggcgc tccaaataca tctcagtgga 18660 ttgcagaagg tgtaaaaaat acaactggtg aggaacacgt aacagaagag gaaaccaata 18720 ctactactta cacttttggc aatgctcctg taaaagctga agctgaaatt acaaaagaag 18780 gactcccagt aggtttggaa gtttcagatg aagaaagtaa accgatttat gctgataaaa 18840 catatcagcc agaacctcag ctgggagatg aaacttggac tgaccttgat ggaaaaaccg 18900 aaaagtatgg aggcagggct ctcaaacccg atactaagat gaaaccatgc tacgggtcct 18960 ttgccaaacc tactaatgtg aaaggcggtc aggcaaaaca aaaaacaacg gagcagccaa 19020 atcagaaagt cgaatatgat atcgacatgg agttttttga tgcggcatcg cagaaaacaa 19080 acttaagtcc taaaattgtc atgtatgcag aaaatgtaaa tttggaaact ccagacactc 19140 atgtagtgta caaacctgga acagaagaca caagttccga agctaatttg ggacaacaat 19200 ctatgcccaa cagacccaac tacattggct tcagagataa ctttattgga cttatgtact 19260 ataacagtac tggtaacatg ggggtgctgg ctggtcaagc gtctcagtta aatgcagtgg 19320 ttgacttgca ggacagaaac acagaacttt cttaccaact cttgcttgac tctctgggcg 19380 acagaaccag atactttagc atgtggaatc aggctgtgga cagttatgat cctgatgtac 19440 gtgttattga aaatcatggt gtggaagatg aacttcccaa ctactgtttt ccactggacg 19500 gcataggtgt tccaacaacc agttacaaat caatagttcc aaatggagac aatgcgccta 19560 attggaagga acctgaagta aatggaacaa gtgagatcgg acagggtaat ttgtttgcca 19620 tggaaattaa ccttcaagcc aatctatggc gaagtttcct ttattccaat gtggctctat 19680 atctcccaga ctcgtacaaa tacaccccgt ccaatgtcac tcttccagaa aacaaaaaca 19740 cctacgacta catgaacggg cgggtggtgc cgccatctct agtagacacc tatgtgaaca 19800 ttggtgccag gtggtctctg gatgccatgg acaatgtcaa cccattcaac caccaccgta 19860 acgctggctt gcgttaccga tccatgcttc tgggtaacgg acgttatgtg cctttccaca 19920 tacaagtgcc tcaaaaattc ttcgctgtta aaaacctgct gcttctccca ggctcctaca 19980 cttatgagtg gaactttagg aaggatgtga acatggttct acagagttcc ctcggtaacg 20040 acctgcgggt agatggcgcc agcatcagtt tcacgagcat caacctctat gctacttttt 20100 tccccatggc tcacaacacc gcttccaccc ttgaagccat gctgcggaat gacaccaatg 20160 atcagtcatt caacgactac ctatctgcag ctaacatgct ctaccccatt cctgccaatg 20220 caaccaatat tcccatttcc attccttctc gcaactgggc ggctttcaga ggctggtcat 20280 ttaccagact gaaaaccaaa gaaactccct ctttggggtc tggatttgac ccctactttg 20340 tctattctgg ttctattccc tacctggatg gtaccttcta cctgaaccac acttttaaga 20400 aggtttccat catgtttgac tcttcagtga gctggcctgg aaatgacagg ttactatctc 20460 ctaacgaatt tgaaataaag cgcactgtgg atggcgaagg ctacaacgta gcccaatgca 20520 acatgaccaa agactggttc ttggtacaga tgctcgccaa ctacaacatc ggctatcagg 20580 gcttctacat tccagaagga tacaaagatc gcatgtattc atttttcaga aacttccagc 20640 ccatgagcag gcaggtggtt gatgaggtca attacaaaga cttcaaggcc gtcgccatac 20700 cctaccaaca caacaactct ggctttgtgg gttacatggc tccgaccatg cgccaaggtc 20760 aaccctatcc cgctaactat ccctatccac tcattggaac aactgccgta aatagtgtta 20820 cgcagaaaaa gttcttgtgt gacagaacca tgtggcgcat accgttctcg agcaacttca 20880 tgtctatggg ggcccttaca gacttgggac agaatatgct ctatgccaac tcagctcatg 20940 ctctggacat gacctttgag gtggatccca tggatgagcc caccctgctt tatcttctct 21000 tcgaagtttt cgacgtggtc agagtgcatc agccacaccg cggcatcatc gaggcagtct 21060 acctgcgtac accgttctcg gccggtaacg ctaccacgta agaagcttct tgcttcttgc 21120 aaatagcagc tgcaaccatg gcctgcggat cccaaaacgg ctccagcgag caagagctca 21180 gagccattgt ccaagacctg ggttgcggac cctatttttt gggaacctac gataagcgct 21240 tcccggggtt catggccccc gataagctcg cctgtgccat tgtaaatacg gccggacgtg 21300 agacgggggg agagcactgg ttggctttcg gttggaaccc acgttctaac acctgctacc 21360 tttttgatcc ttttggattc tcggatgatc gtctcaaaca gatttaccag tttgaatatg 21420 agggtctcct gcgccgcagc gctcttgcta ccaaggaccg ctgtattacg ctggaaaaat 21480 ctacccagac cgtgcagggt ccccgttctg ccgcctgcgg acttttctgc tgcatgttcc 21540 ttcacgcctt tgtgcactgg cctgaccgtc ccatggacgg aaaccccacc atgaaattgc 21600 taactggagt gccaaacaac atgcttcatt ctcctaaagt ccagcccacc ctgtgtgaca 21660 atcaaaaagc actctaccat tttcttaata cccattcgcc ttattttcgc tcccatcgta 21720 cacacatcga aagggccact gcgttcgacc gtatggatgt tcaataatga ctcatgtaaa 21780 caacgtgttc aataaacatc actttatttt tttacatgta tcaaggctct gcattactta 21840 tttatttaca agtcgaatgg gttctgacga gaatcagaat gacccgcagg cagtgatacg 21900 ttgcggaact gatacttggg ttgccacttg aattcgggaa tcaccaactt gggaaccggt 21960 atatcgggca ggatgtcact ccacagcttt ctggtcagct gcaaagctcc aagcaggtca 22020 ggagccgaaa tcttgaaatc acaattagga ccagtgcttt gagcgcgaga gttgcggtac 22080 accggattgc agcactgaaa caccatcagc gacggatgtc tcacgcttgc cagcacggtg 22140 ggatctgcaa tcatgcccac atccagatct tcagcattgg caatgctgaa cggggtcatc 22200 ttgcaggtct gcctacccat ggcgggcacc caattaggct tgtggttgca atcgcagtgc 22260 agggggatca gtatcatctt ggcctgatcc tgtctgattc ctggatacac ggctctcatg 22320 aaagcatcat attgcttgaa agcctgctgg gctttactac cctcggtata aaacatcccg 22380 caggacctgc tcgaaaactg gttagctgca cagccggcat cattcacaca gcagcgggcg 22440 tcattgttag ctatttgcac cacacttctg ccccagcggt tttgggtgat tttggttcgc 22500 tcgggattct cctttaaggc tcgttgtccg ttctcgctgg ccacatccat ctcgataatc 22560 tgctccttct gaatcataat attgccatgc aggcacttca gcttgccctc ataatcattg 22620 cagccatgag gccacaacgc acagcctgta cattcccaat tatggtgggc gatctgagaa 22680 aaagaatgta tcattccctg cagaaatctt cccatcatcg tgctcagtgt cttgtgacta 22740 gtgaaagtta actggatgcc tcggtgctcc tcgtttacgt actggtgaca gatgcgcttg 22800 tattgttcgt gttgctcagg cattagttta aaagaggttc taagttcgtt atccagcctg 22860 tacttctcca tcagcagaca catcacttcc atgcctttct cccaagcaga caccaggggc 22920 aagctaatcg gattcttaac agtgcaggca gcagctcctt tagccagagg gtcatcttta 22980 gcgatcttct caatgcttct tttgccatcc ttctcaacga tgcgcacggg cgggtagctg 23040 aaacccactg ctacaagttg cgcctcttct ctttcttctt cgctgtcttg actgatgtct 23100 tgcatgggga tatgtttggt cttccttggc ttctttttgg ggggtatcgg aggaggagga 23160 ctgtcgctcc gttccggaga cagggaggat tgtgacgttt cgctcaccat taccaactga 23220 ctgtcggtag aagaacctga ccccacacgg cgacaggtgt ttctcttcgg gggcagaggt 23280 ggaggcgatt gcgaagggct gcggtccgac ctggaaggcg gatgactggc agaacccctt 23340 ccgcgttcgg gggtgtgctc cctgtggcgg tcgcttaact gatttccttc gcggctggcc 23400 attgtgttct cctaggcaga gaaacaacag acatggaaac tcagccattg ctgtcaacat 23460 cgccacgagt gccatcacat ctcgtcctca gcgacgagga aaaggagcag agcttaagca 23520 ttccaccgcc cagtcctgcc accacctcta ccctagaaga taaggaggtc gacgcatctc 23580 atgacatgca gaataaaaaa gcgaaagagt ctgagacaga catcgagcaa gacccgggct 23640 atgtgacacc ggtggaacac gaggaagagt tgaaacgctt tctagagaga gaggatgaaa 23700 actgcccaaa acaacgagca gataactatc accaagatgc tggaaatagg gatcagaaca 23760 ccgactacct catagggctt gacggggaag acgcgctcct taaacatcta gcaagacagt 23820 cgctcatagt caaggatgca ttattggaca gaactgaagt gcccatcagt gtggaagagc 23880 tcagccgcgc ctacgagctt aacctctttt cacctcgtac tccccccaaa cgtcagccaa 23940 acggcacctg cgagccaaat cctcgcttaa acttttatcc agcttttgct gtgccagaag 24000 tactggctac ctatcacatc ttttttaaaa atcaaaaaat tccagtctcc tgccgcgcta 24060 atcgcacccg cgccgatgcc ctactcaatc tgggacctgg ttcacgctta cctgatatag 24120 cttccttgga agaggttcca aagatcttcg agggtctggg caataatgag actcgggccg 24180 caaatgctct gcaaaaggga gaaaatggca tggatgagca tcacagcgtt ctggtggaat 24 240 tggaaggcga taatgccaga ctcgcagtac tcaagcgaag catcgaggtc acacacttcg 24300 catatcccgc tgtcaacctg ccccctaaag tcatgacggc ggtcatggac cagttactca 24360 ttaagcgcgc aagtcccctt tcagaagaca tgcatgaccc agatgcctgt gatgagggta 24420 aaccagtggt cagtgatgag cagctaaccc gatggctggg caccgactct cccagggatt 24480 tggaagagcg tcgcaagctt atgatggccg tggtgctggt taccgtagaa ctagagtgtc 24540 tccgacgttt ctttaccgat tcagaaacct tgcgcaaact cgaagagaat ctgcactaca 24600 cttttagaca cggctttgtg cggcaggcat gcaagatatc taacgtggaa ctcaccaacc 24660 tggtttccta catgggtatt ctgcatgaga atcgcctagg acaaagcgtg ctgcacagca 24720 ccctgaaggg ggaagcccgc cgtgattaca tccgcgattg tgtctatctg tacctgtgcc 24780 acacgtggca aaccggcatg ggtgtatggc agcaatgttt agaagaacag aacttgaaag 24840 agcttgacaa gctcttacag aaatctctta aggttctgtg gacagggttc gacgagcgca 24900 ccgtcgcttc cgacctggca gacctcatct tcccagagcg tctcagggtt actttgcgaa 24960 acggattgcc tgactttatg agccagagca tgcttaacaa ttttcgctct ttcatcctgg 25020 aacgctccgg tatcctgccc gccacctgct gcgcactgcc ctccgacttt gtgcctctca 25080 cctaccgcga gtgccccccg ccgctatgga gtcactgcta cctgttccgt ctggccaact 25 140 atctctccta ccactcggat gtgatcgagg atgtgagcgg agacggcttg ctggagtgtc 25200 actgccgctg caatctgtgc acgccccacc ggtccctagc ttgcaacccc cagttgatga 25260 gcgaaaccca gataataggc acctttgaat tgcaaggccc cagcagccaa ggcgatgggt 25320 cttctcctgg gcaaagttta aaactgaccc cgggactgtg gacctccgcc tacttgcgca 25380 agtttgctcc ggaagattac cacccctatg aaatcaagtt ctatgaggac caatcacagc 25440 ctccaaaggc cgaactttcg gcctgcgtca tcacccaggg ggcaattctg gcccaattgc 25500 aagccatcca aaaatcccgc caagaatttc tactgaaaaa gggtaagggg gtctaccttg 25560 acccccagac cggcgaggaa ctcaacacaa ggttccctca ggatgtccca acgacgagaa 25620 aacaagaagt tgaaggtgca gccgccgccc ccagaagata tggaggaaga ttgggacagt 25680 caggcagagg aggcggagga ggacagtctg gaggacagtc tggaggaaga cagtttggag 25740 gaggaaaacg aggaggcaga ggaggtggaa gaagtaaccg ccgacaaaca gttatcctcg 25800 gctgcggaga caagcaacag cgctaccatc tccgctccga gtcgaggaac ccggcggcgt 25860 cccagcagta gatgggacga gaccggacgc ttcccgaacc caaccagcgc ttccaagacc 25920 ggtaagaagg atcggcaggg atacaagtcc tggcgggggc ataagaatgc catcatctcc 25980 tgcttgcatg agtgcggggg caacatatcc ttcacgcggc gctacttgct attccaccat 26040 ggggtgaact ttccgcgcaa tgttttgcat tactaccgtc acctccacag cccctactat 26100 agccagcaaa tcccggcagt ctcgacagat aaagacagcg gcggcgacct ccaacagaaa 26160 accagcagcg gcagttagaa aatacacaac aagtgcagca acaggaggat taaagattac 26220 agccaacgag ccagcgcaaa cccgagagtt aagaaatcgg atctttccaa ccctgtatgc 26280 catcttccag cagagtcggg gtcaagagca ggaactgaaa ataaaaaacc gatctctgcg 26340 ttcgctcacc agaagttgtt tgtatcacaa gagcgaagat caacttcagc gcactctcga 26400 ggacgccgag gctctcttca acaagtactg cgcgctgact cttaaagagt aggcagcgac 26460 cgcgcttatt caaaaaaggc gggaattaca tcatcctcga catgagtaaa gaaattccca 26520 cgccttacat gtggagttat caaccccaaa tgggattggc ggcaggcgcc tcccaggact 26580 actccacccg catgaattgg ctcagcgccg ggccttctat gatttctcga gttaatgata 26640 tacgcgccta ccgaaaccaa atacttttgg aacagtcagc tcttaccacc acgccccgcc 26700 aacaccttaa tcccagaaat tggcccgccg ccctagtgta ccaggaaagt cccgctccca 26760 ccactgtatt acttcctcga gacgcccagg ccgaagtcca aatgactaat gcaggtgcgc 26820 agttagctgg cggctccacc ctatgtcgtc acaggcctcg gcataatata aaacgcctga 26880 tgatcagagg ccgaggtatc cagctcaacg acgagtcggt gagctctccg cttggtctac 26940 gaccagacgg aatctttcag attgccggct gcgggagatc ttccttcacc cctcgtcagg 27000 ctgttctgac tttggaaagt tcgtcttcgc aaccccgctc gggcggaatc gggaccgttc 27060 aatttgtgga ggagtttact ccctctgtct acttcaaccc cttctccgga tctcctgggc 27120 attacccgga cgagttcata ccgaacttcg acgcgattag cgagtcagtg gacggctacg 27180 attgatgtct ggtgacgcgg ctgagctatc tcggctgcga catctagacc actgccgccg 27240 ctttcgctgc tttgcccggg aactcattga gttcatctac ttcgaactcc ccaaggatca 27300 ccctcaaggt ccggcccacg gagtgcggat ttctatcgaa ggcaaaatag actctcgcct 27360 gcaacgaatt ttctcccagc ggcccgtgct gatcgagcga gaccagggaa acaccacggt 27420 ttccatctac tgcatttgta atcaccccgg attgcatgaa agcctttgct gtcttatgtg 27480 tactgagttt aataaaaact gaattaagac tctcctacgg actgccgctt cttcaacccg 27540 gattttacaa ccagaagaac gaaacttttc ctgtcgtcca ggactctgtt aacttcacct 27600 ttcctactca caaactagaa gctcaacgac tacaccgctt ttccagaagc attttcccta 27660 ctaatactac tttcaaaacc ggaggtgagc tccaaggtct tcctacagaa aacccttggg 27720 tggaagcggg ccttgtagtg ctaggaattc ttgcgggtgg gcttgtgatt attctttgct 27780 acctatacac accttgcttc actttcttag tggtgttgtg gtattggttt aaaaaatggg 27840 gcccatacta gtcttgcttg ttttactttc gcttttggaa ccgggttctg ccaattacga 27900 tccatgtcta gacttcgacc cagaaaactg cacacttact tttgcacccg acacaagccg 27960 catctgtgga gttcatcgcc tctcttacga acttggcccc caacgacaaa aatttacctg 28020 catggtggga atcaacccca tagttatcac ccagcaaagt ggagatacta agggttgcat 28080 tcactgctcc tgcgattcca tcgagtgcac ctacaccctg ctgaagaccc tatgcggcct 28140 aagagacctg ctaccaatga attaaaaaat gattaataaa aaatcactta cttgaaatca 28200 gcaataaggt ctctgttgaa attttctccc agcagcacct cacttccctc ttcccaactc 28260 tggtattcta aaccccgttc agcggcatac tttctccata ctttaaaggg gatgtcaaat 28320 tttagctcct ctcctgtacc cacaatcttc atgtctttct tcccagatga ccaagagagt 28380 ccggctcagt gactccttca accctgtcta cccctatgaa gatgaaagca cctcccaaca 28440 cccctttata aacccagggt ttatttcccc aaatggcttc acacaaagcc caaacggagt 28500 tcttacttta aaatgtttaa ccccactaac aaccacaggc ggatctctac agctaaaagt 28560 gggaggggga cttacagtgg atgacaccaa cggttttttg aaagaaaaca taagtgccac 28620 cacaccactc gttaagactg gtcactctat aggtttacca ctaggagccg gattgggaac 28680 gaatgaaaat aaactttgta tcaaattagg acaaggactt acattcaatt caaacaacat 28740 ttgcattgat gacaatatta acaccttatg gacaggagtc aaccccaccg aagccaactg 28800 tcaaatcatg aactccagtg aatctaatga ttgcaaatta attctaacac tagttaaaac 28860 tggagcacta gtcactgcat ttgtttatgt tataggagta tctaacaatt ttaatatgct 28920 aactacacac agaaatataa attttactgc agagctgttt ttcgattcta ctggtaattt 28980 actaactaga ctctcatccc tcaaaactcc acttaatcat aaatcaggac aaaacatggc 29040 tactggtgcc attactaatg ctaaaggttt catgcccagc acgactgcct atcctttcaa 29100 tgataattct agagaaaaag aaaactacat ttacggaact tgttactaca cagctagtga 29160 tcgcactgct tttcccattg acatatctgt catgcttaac cgaagagcaa taaatgacga 29220 gacatcatat tgtattcgta taacttggtc ctggaacaca ggagatgccc cagaggtgca 29280 aacctctgct acaaccctag tcacctcccc atttaccttt tactacatca gagaagacga 29340 ctgacaaata aagtttaact tgtttatttg aaaatcaatt cacaaaatcc gagtagttat 29400 tttgcctccc ccttcccatt taacagaata caccaatctc tccccacgca cagctttaaa 29460 catttggata ccattagata tagacatggt tttagattcc acattccaaa cagtttcaga 29520 gcgagccaat ctggggtcag tgatagataa aaatccatcg ggatagtctt ttaaagcgct 29580 ttcacagtcc aactgctgcg gatgcgactc cggagtctgg atcacggtca tctggaagaa 29640 gaacgatggg aatcataatc cgaaaacggt atcggacgat tgtgtctcat caaacccaca 29700 agcagccgct gtctgcgtcg ctccgtgcga ctgctgttta tgggatcagg gtccacagtg 29760 tcctgaagca tgattttaat agcccttaac atcaactttc tggtgcgatg cgcgcagcaa 29820 cgcattctga tttcactcaa atctttgcag taggtacaac acattattac aatattgttt 29880 aataaaccat aattaaaagc gctccagcca aaactcatat ctgatataat cgcccctgca 29940 tgaccatcat accaaagttt aatataaatt aaatgacgtt ccctcaaaaa cacactaccc 30000 acatacatga tctcttttgg catgtgcata ttaacaatct gtctgtacca tggacaacgt 30060 tggttaatca tgcaacccaa tataaccttc cggaaccaca ctgccaacac cgctccccca 30120 gccatgcatt gaagtgaacc ctgctgatta caatgacaat gaagaaccca attctctcga 30180 ccgtgaatca cttgagaatg aaaaatatct atagtggcac aacatagaca taaatgcatg 30240 catcttctca taatttttaa ctcctcagga tttagaaaca tatcccaggg aataggaagc 30300 tcttgcagaa cagtaaagct ggcagaacaa ggaagaccac gaacacaact tacactatgc 30360 atagtcatag tatcacaatc tggcaacagc gggtggtctt cagtcataga agctcgggtt 30420 tcattttcct cacaacgtgg taactgggct ctggtgtaag ggtgatgtct ggcgcatgat 30480 gtcgagcgtg cgcgcaacct tgtcataatg gagttgcttc ctgacattct cgtattttgt 30540 atagcaaaac gcggccctgg cagaacacac tcttcttcgc cttctatcct gccgcttagc 30600 gtgttccgtg tgatagttca agtacaacca cactcttaag ttggtcaaaa gaatgctggc 30660 ttcagttgta atcaaaactc catcgcatct aatcgttctg aggaaatcat ccaagcaatg 30720 caactggatt gtgtttcaag caggagagga gagggaagag acggaagaac catgttaatt 30780 tttattccaa acgatctcgc agtacttcaa attgtagatc gcgcagatgg catctctcgc 30840 ccccactgtg ttggtgaaaa agcacagcta gatcaaaaga aatgcgattt tcaaggtgct 30900 caacggtggc ttccagcaaa gcctccacgc gcacatccaa gaacaaaaga ataccaaaag 30960 aaggagcatt ttctaactcc tcaatcatca tattacattc ctgcaccatt cccagataat 31020 tttcagcttt ccagccttga attattcgtg tcagttcttg tggtaaatcc aatccacaca 31080 ttacaaacag gtcccggagg gcgccctcca ccaccattct taaacacacc ctcataatga 31140 caaaatatct tgctcctgtg tcacctgtag cgaattgaga atggcaacat caattgacat 31200 gcccttggct ctaagttctt ctttaagttc tagttgtaaa aactctctca tattatcacc 31260 aaactgctta gccagaagcc ccccgggaac aagagcaggg gacgctacag tgcagtacaa 31320 gcgcagacct ccccaattgg ctccagcaaa aacaagattg gaataagcat attgggaacc 31380 gccagtaata tcatcgaagt tgctggaaat ataatcaggc agagtttctt gtaaaaattg 31440 aataaaagaa aaatttgcca aaaaaacatt caaaacctct gggatgcaaa tgcaataggt 31500 taccgcgctg cgctccaaca ttgttagttt tgaattagtc tgcaaaaata aaaaaaaaaa 31560 caagcgtcat atcatagtag cctgacgaac agatggataa atcagtcttt ccatcacaag 31620 acaagccaca gggtctccag ctcgaccctc gtaaaacctg tcatcatgat taaacaacag 31680 caccgaaagt tcctcgcggt gaccagcatg aataattctt gatgaagcat acaatccaga 31740 catgttagca tcagttaacg agaaaaaaca gccaacatag cctttgggta taattatgct 31800 taatcgtaag tatagcaaag ccacccctcg cggatacaaa gtaaaaggca caggagaata 31860 aaaaatataa ttatttctct gctgctgttc aggcaacgtc gcccccggtc cctctaaata 31920 cacatacaaa gcctcatcag ccatggctta ccagacaaag tacagcgggc acacaaagca 31980 caagctctaa agtgactctc caacctctcc acaatatata tatacacaag ccctaaactg 32040 acgtaatggg agtaaagtgt aaaaaatccc gccaaaccca acacacaccc cgaaactgcg 32 100 tcaccaggga aaagtacagt ttcacttccg caatcccaac aggcgtaact tcctctttct 32160 cacggtacgt gatatcccac taacttgcaa cgtcattttc ccacggtcgc accgcccctt 32220 ttagccgtta accccacagc caatcaccac acgatccaca ctttttaaaa tcacctcatt 32280 tacatattgg caccattcca tctataaggt atattatata gataga 32326 <210> 22 <211> 5288 <212> DNA <213> Artificial Sequence <220> <223> DNA SEQUENCE CORRESPONDING TO E2B REGION OF THE ENAD GENOME (BP 10355-5068) <400> 22 ctatggcatc tcgatccagc agacctcctc gtttcgcggg tttggacggc tcctggaata 60 gggtatgaga cgatgggcgt ccagcgctgc cagggttcgg tccttccagg gtctcagtgt 120 tcgagtcagg gttgtttccg tcacagtgaa ggggtgtgcg cctgcttggg cgcttgccag 180 ggtgcgcttc agactcatcc tgctggtcga aaacttctgt cgcttggcgc cctgtatgtc 240 ggccaagtag cagtttacca tgagttcgta gttgagcgcc tcggctgcgt ggcctttggc 300 gcggagctta cctttggaag ttttcttgca taccgggcag tataggcatt tcagcgcata 360 caacttgggc gcaaggaaaa cggattctgg ggagtatgca tctgcgccgc aggaggcgca 420 aacagtttca cattccacca gccaggttaa atccggttca ttggggtcaa aaacaagttt 480 tccgccatat tttttgatgc gtttcttacc tttggtctcc atgagttcgt gtcctcgttg 540 agtgacaaac aggctgtccg tgtccccgta gactgatttt acaggcctct tctccagtgg 600 agtgcctcgg tcttcttcgt acaggaactc tgaccactct gatacaaagg cgcgcgtcca 660 ggccagcaca aaggaggcta tgtgggaggg gtagcgatcg ttgtcaacca gggggtccac 720 cttttccaaa gtatgcaaac acatgtcacc ctcttcaaca tccaggaatg tgattggctt 780 gtaggtgtat ttcacgtgac ctggggtccc cgctgggggg gtataaaagg gggcggttct 840 ttgctcttcc tcactgtctt ccggatcgct gtccaggaac gtcagctgtt ggggtaggta 900 ttccctctcg aaggcgggca tgacctctgc actcaggttg tcagtttcta agaacgagga 960 ggatttgata ttgacagtgc cggttgagat gcctttcatg aggttttcgt ccatctggtc 1020 agaaaacaca atttttttat tgtcaagttt ggtggcaaat gatccataca gggcgttgga 1080 taaaagtttg gcaatggatc gcatggtttg gttcttttcc ttgtccgcgc gctctttggc 1140 ggcgatgttg agttggacat actcgcgtgc caggcacttc cattcgggga agatagttgt 1200 taattcatct ggcacgattc tcacttgcca ccctcgatta tgcaaggtaa ttaaatccac 1260 actggtggcc acctcgcctc gaaggggttc attggtccaa cagagcctac ctcctttcct 1320 agaacagaaa gggggaagtg ggtctagcat aagttcatcg ggagggtctg catccatggt 1380 aaagattccc ggaagtaaat ccttatcaaa atagctgatg ggagtggggt catctaaggc 1440 catttgccat tctcgagctg ccagtgcgcg ctcatatggg ttaaggggac tgccccatgg 1500 catgggatgg gtgagtgcag aggcatacat gccacagatg tcatagacgt agatgggatc 1560 ctcaaagatg cctatgtagg ttggatagca tcgcccccct ctgatacttg ctcgcacata 1620 gtcatatagt tcatgtgatg gcgctagcag ccccggaccc aagttggtgc gattgggttt 1680 ttctgttctg tagacgatct ggcgaaagat ggcgtgagaa ttggaagaga tggtgggtct 1740 ttgaaaaatg ttgaaatggg catgaggtag acctacagag tctctgacaa agtgggcata 1800 agattcttga agcttggtta ccagttcggc ggtgacaagt acgtctaggg cgcagtagtc 1860 aagtgtttct tgaatgatgt cataacctgg ttggtttttc ttttcccaca gttcgcggtt 1920 gagaaggtat tcttcgcgat ccttccagta ctcttctagc ggaaacccgt ctttgtctgc 1980 acggtaagat cctagcatgt agaactgatt aactgccttg taagggcagc agcccttctc 2040 tacgggtaga gagtatgctt gagcagcttt tcgtagcgaa gcgtgagtaa gggcaaaggt 2100 gtctctgacc atgactttga ggaattggta tttgaagtcg atgtcgtcac aggctccctg 2160 ttcccagagt tggaagtcta cccgtttctt gtaggcgggg ttgggcaaag cgaaagtaac 2220 atcattgaag agaatcttgc cggccctggg catgaaattg cgagtgatgc gaaaaggctg 2280 tggtacttcc gctcggttat tgataacctg ggcagctagg acgatctcgt cgaaaccgtt 2340 gatgttgtgt cctacgatgt ataattctat gaaacgcggc gtgcctctga cgtgaggtag 2400 cttactgagc tcatcaaagg ttaggtctgt ggggtcagat aaggcgtagt gttcgagagc 2460 ccattcgtgc aggtgaggat tcgctttaag gaaggaggac cagaggtcca ctgccagtgc 2520 tgtttgtaac tggtcccggt actgacgaaa atgccgtccg actgccattt tttctggggt 2580 gacgcaatag aaggtttggg ggtcctgccg ccagcgatcc cacttgagtt ttatggcgag 2640 gtcataggcg atgttgacga gccgctggtc tccagagagt ttcatgacca gcatgaaggg 2700 gattagctgc ttgccaaagg accccatcca ggtgtaggtt tccacatcgt aggtgagaaa 2760 gagcctttct gtgcgaggat gagagccaat cgggaagaac tggatctcct gccaccagtt 2820 ggaggaatgg ctgttgatgt gatggaagta gaactccctg cgacgcgccg agcattcatg 2880 cttgtgcttg tacagacggc cgcagtagtc gcagcgttgc acgggttgta tctcgtgaat 2940 gagttgtacc tggcttccct tgacgagaaa tttcagtggg aagccgaggc ctggcgattg 3000 tatctcgtgc tttactatgt tgtctgcatc ggcctgttca tcttctgtct cgatggtggt 3060 catgctgacg agccctcgcg ggaggcaagt ccagacctcg gcgcggcagg ggcggagctc 3120 gaggacgaga gcgcgcaggc tggagctgtc cagggtcctg agacgctgcg gactcaggtt 3180 agtaggcagt gtcaggagat taacttgcat gatcttttgg agggcgtgcg ggaggttcag 3240 atagtacttg atctcaacgg gtccgttggt ggagatgtcg atggcttgca gggttccgtg 3300 tcccttgggc gctaccaccg tgcccttgtt tttcattttg gacggcggtg gctctgttgc 3360 ttcttgcatg tttagaagcg gtgtcgaggg cgcgcaccgg gcggcagggg cggctcggga 3420 cccggcggca tggctggcag tggtacgtcg gcgccgcgcg cgggtaggtt ctggtactgc 3480 gccctgagaa gactcgcatg cgcgacgacg cggcggttga catcctggat ctgacgcctc 3540 tgggtgaaag ctaccggccc cgtgagcttg aacctgaaag agagttcaac agaatcaatc 3600 tcggtatcgt tgacggcggc ttgcctaagg atttcttgca cgtcaccaga gttgtcctgg 3660 taggcgatct ccgccatgaa ctgctcgatc tcttcctctt gaagatctcc gcggcccgct 3720 ctctcgacgg tggccgcgag gtcgttggag atgcgcccaa tgagttgaga gaatgcattc 3780 atgcccgcct cgttccagac gcggctgtag accacggccc ccacgggatc tctcgcgcgc 3840 atgaccacct gggcgaggtt gagctccacg tggcgggtga agaccgcata gttgcatagg 3900 cgctggaaaa ggtagttgag tgtggtggcg atgtgctcgg tgacgaagaa atacatgatc 3960 catcgtctca gcggcatctc gctgacatcg cccagagctt ccaagcgctc catggcctcg 4020 tagaagtcca cggcaaaatt aaaaaactgg gagtttcgcg cggacacggt caactcctct 4080 tccagaagac ggataagttc ggcgatggtg gtgcgcacct cgcgctcgaa agcccctggg 4140 atttcttcct caatctcttc ttcttccact aacatctctt cctcttcagg tggggctgca 4200 ggaggagggg gaacgcggcg acgccggcgg cgcacgggca gacggtcgat gaatctttca 4260 atgacctctc cgcggcggcg gcgcatggtt tcagtgacgg cgcggccgtt ctcgcgcggt 4320 cgcagagtaa aaacaccgcc gcgcatctcc ttaaagtggt gactgggagg ttctccgttt 4380 gggagggaga gggcgctgat tatacatttt attaattggc ccgtagggac tgcacgcaga 4440 gatctgatcg tgtcaagatc cacgggatct gaaaaccttt cgacgaaagc gtctaaccag 4500 tcacagtcac aaggtaggct gagtacggct tcttgtgggc gggggtggtt atgtgttcgg 4560 tctgggtctt ctgtttcttc ttcatctcgg gaaggtgaga cgatgctgct ggtgatgaaa 4620 ttaaagtagg cagttctaag acggcggatg gtggcgagga gcaccaggtc tttgggtccg 4680 gcttgctgga tacgcaggcg attggccatt ccccaagcat tatcctgaca tctagcaaga 4740 tctttgtagt agtcttgcat gagccgttct acgggcactt cttcctcacc cgttctgcca 4800 tgcatacgtg tgagtccaaa tccgcgcatt ggttgtacca gtgccaagtc agctacgact 4860 ctttcggcga ggatggcttg ctgtacttgg gtaagggtgg cttgaaagtc atcaaaatcc 4920 acaaagcggt ggtaagctcc tgtattaatg gtgtaagcac agttggccat gactgaccag 4980 ttaactgtct ggtgaccagg gcgcacgagc tcggtgtatt taaggcgcga ataggcgcgg 5040 gtgtcaaaga tgtaatcgtt gcaggtgcgc accagatact ggtaccctat aagaaaatgc 5100 ggcggtggtt ggcggtagag aggccatcgt tctgtagctg gagcgccagg ggcgaggtct 5160 tccaacataa ggcggtgata gccgtagatg tacctggaca tccaggtgat tcctgcggcg 5220 gtagtagaag cccgaggaaa ctcgcgtacg cggttccaaa tgttgcgtag cggcatgaag 5280 tagttcat 5288 <210> 23 <211> 981 <212> DNA <213> Artificial Sequence <220> <223> E3 REGION FROM ENAD <400> 23 atgtctggtg acgcggctga gctatctcgg ctgcgacatc tagaccactg ccgccgcttt 60 cgctgctttg cccgggaact cattgagttc atctacttcg aactccccaa ggatcaccct 120 caaggtccgg cccacggagt gcggatttct atcgaaggca aaatagactc tcgcctgcaa 180 cgaattttct cccagcggcc cgtgctgatc gagcgagacc agggaaacac cacggtttcc 240 atctactgca tttgtaatca ccccggattg catgaaagcc tttgctgtct tatgtgtact 300 gagtttaata aaaactgaat taagactctc ctacggactg ccgcttcttc aacccggatt 360 ttacaaccag aagaacgaaa cttttcctgt cgtccaggac tctgttaact tcacctttcc 420 tactcacaaa ctagaagctc aacgactaca ccgcttttcc agaagcattt tccctactaa 480 tactactttc aaaaccggag gtgagctcca aggtcttcct acagaaaacc cttgggtgga 540 agcgggcctt gtagtgctag gaattcttgc gggtgggctt gtgattattc tttgctacct 600 atacacacct tgcttcactt tcttagtggt gttgtggtat tggtttaaaa aatggggccc 660 atactagtct tgcttgtttt actttcgctt ttggaaccgg gttctgccaa ttacgatcca 720 tgtctagact tcgacccaga aaactgcaca cttacttttg cacccgacac aagccgcatc 780 tgtggagttc atcgcctctc ttacgaactt ggcccccaac gacaaaaatt tacctgcatg 840 gtgggaatca accccatagt tatcacccag caaagtggag atactaaggg ttgcattcac 900 tgctcctgcg attccatcga gtgcacctac accctgctga agaccctatg cggcctaaga 960 gacctgctac caatgaatta a 981 <210> 24 <211> 201 <212> DNA <213> Artificial Sequence <220> <223> A NON-CODING SEQUENCE SUITABLE FOR INCLUSION INTO BX <400> 24 aaaatgatta ataaaaaatc acttacttga aatcagcaat aaggtctctg ttgaaatttt 60 ctcccagcag cacctcactt ccctcttccc aactctggta ttctaaaccc cgttcagcgg 120 catactttct ccatacttta aaggggatgt caaattttag ctcctctcct gtacccacaa 180 tcttcatgtc tttcttccca g 201 <210> 25 <211> 34 <212> DNA <213> Artificial Sequence <220> <223> A NON-CODING SEQUENCE SUITABLE FOR INCLUSION INTO BY <400> 25 caaataaagt ttaacttgtt tatttgaaaa tcaa 34 <210> 26 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Hinge linker sequences <400> 26 Asp Lys Thr His Thr Cys Ala Ala 1 5 <210> 27 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Hinge linker sequence <400> 27 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 1 5 10 <210> 28 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> Hinge linker sequence <400> 28 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Thr Cys Pro Pro Cys 1 5 10 15 Pro Ala <210> 29 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> Hinge linker sequence <400> 29 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Thr Cys Pro Pro Cys 1 5 10 15 Pro Ala Thr Cys Pro Pro Cys Pro Ala 20 25 <210> 30 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> Hinge linker sequence <400> 30 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Gly Lys Pro Thr Leu 1 5 10 15 Tyr Asn Ser Leu Val Met Ser Asp Thr Ala Gly Thr Cys Tyr 20 25 30 <210> 31 <211> 31 <212> PRT <213> Artificial Sequence <220> <223> Hinge linker sequence <400> 31 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Gly Lys Pro Thr His 1 5 10 15 Val Asn Val Ser Val Val Met Ala Glu Val Asp Gly Thr Cys Tyr 20 25 30 <210> 32 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Hinge linker sequence <400> 32 Asp Lys Thr His Thr Cys Cys Val Glu Cys Pro Pro Cys Pro Ala 1 5 10 15 <210> 33 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> Hinge linker sequence <400> 33 Asp Lys Thr His Thr Cys Pro Arg Cys Pro Glu Pro Lys Ser Cys Asp 1 5 10 15 Thr Pro Pro Pro Cys Pro Arg Cys Pro Ala 20 25 <210> 34 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Hinge linker sequence <400> 34 Asp Lys Thr His Thr Cys Pro Ser Cys Pro Ala 1 5 10 <210> 35 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 35 Ser Gly Gly Gly Gly Ser Glu 1 5 <210> 36 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 36 Asp Lys Thr His Thr Ser 1 5 <210> 37 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 37 Ser Gly Gly Gly Gly Ser 1 5 <210> 38 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 38 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 <210> 39 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 39 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 15 <210> 40 <211> 21 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 40 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 15 Gly Gly Gly Gly Ser 20 <210> 41 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 41 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 15 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 20 25 <210> 42 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 42 Ala Ala Ala Gly Ser Gly Gly Ala Ser Ala Ser 1 5 10 <210> 43 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <220> <221> misc_feature <222> (7)..(7) <223> Xaa can be any naturally occurring amino acid <400> 43 Ala Ala Ala Gly Ser Gly Xaa Gly Gly Gly Ser Gly Ala Ser Ala Ser 1 5 10 15 <210> 44 <211> 21 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <220> <221> misc_feature <222> (7)..(7) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature <222> (12)..(12) <223> Xaa can be any naturally occurring amino acid <400> 44 Ala Ala Ala Gly Ser Gly Xaa Gly Gly Gly Ser Xaa Gly Gly Gly Ser 1 5 10 15 Gly Ala Ser Ala Ser 20 <210> 45 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <220> <221> misc_feature <222> (7)..(7) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature <222> (12)..(12) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature <222> (17)..(17) <223> Xaa can be any naturally occurring amino acid <400> 45 Ala Ala Ala Gly Ser Gly Xaa Gly Gly Gly Ser Xaa Gly Gly Gly Ser 1 5 10 15 Xaa Gly Gly Gly Ser Gly Ala Ser Ala Ser 20 25 <210> 46 <211> 31 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <220> <221> misc_feature <222> (7)..(7) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature <222> (12)..(12) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature <222> (17)..(17) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature <222> (22)..(22) <223> Xaa can be any naturally occurring amino acid <400> 46 Ala Ala Ala Gly Ser Gly Xaa Gly Gly Gly Ser Xaa Gly Gly Gly Ser 1 5 10 15 Xaa Gly Gly Gly Ser Xaa Gly Gly Gly Ser Gly Ala Ser Ala Ser 20 25 30 <210> 47 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <220> <221> misc_feature <222> (7)..(7) <400> 47 Ala Ala Ala Gly Ser Gly Xaa Ser Gly Ala Ser Ala Ser 1 5 10 <210> 48 <211> 28 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 48 Pro Gly Gly Asn Arg Gly Thr Thr Thr Thr Arg Arg Pro Ala Thr Thr 1 5 10 15 Thr Gly Ser Ser Pro Gly Pro Thr Gln Ser His Tyr 20 25 <210> 49 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 49 Ala Thr Thr Thr Gly Ser Ser Pro Gly Pro Thr 1 5 10 <210> 50 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 50 Ala Thr Thr Thr Gly Ser 1 5 <210> 51 <211> 21 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 51 Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Ser Pro Pro Ser Lys Glu 1 5 10 15 Ser His Lys Ser Pro 20 <210> 52 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 52 Gly Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 1 5 10 15 <210> 53 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 53 Gly Gly Gly Gly Ile Ala Pro Ser Met Val Gly Gly Gly Gly Ser 1 5 10 15 <210> 54 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 54 Gly Gly Gly Gly Lys Val Glu Gly Ala Gly Gly Gly Gly Gly Ser 1 5 10 15 <210> 55 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 55 Gly Gly Gly Gly Ser Met Lys Ser His Asp Gly Gly Gly Gly Ser 1 5 10 15 <210> 56 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 56 Gly Gly Gly Gly Asn Leu Ile Thr Ile Val Gly Gly Gly Gly Ser 1 5 10 15 <210> 57 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 57 Gly Gly Gly Gly Val Val Pro Ser Leu Pro Gly Gly Gly Gly Ser 1 5 10 15 <210> 58 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 58 Gly Gly Glu Lys Ser Ile Pro Gly Gly Gly Gly Ser 1 5 10 <210> 59 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 59 Arg Pro Leu Ser Tyr Arg Pro Pro Phe Pro Phe Gly Phe Pro Ser Val 1 5 10 15 Arg Pro <210> 60 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 60 Tyr Pro Arg Ser Ile Tyr Ile Arg Arg Arg His Pro Ser Pro Ser Leu 1 5 10 15 Thr Thr <210> 61 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 61 Thr Pro Ser His Leu Ser His Ile Leu Pro Ser Phe Gly Leu Pro Thr 1 5 10 15 Phe Asn <210> 62 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 62 Arg Pro Val Ser Pro Phe Thr Phe Pro Arg Leu Ser Asn Ser Trp Leu 1 5 10 15 Pro Ala <210> 63 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 63 Ser Pro Ala Ala His Phe Pro Arg Ser Ile Pro Arg Pro Gly Pro Ile 1 5 10 15 Arg Thr <210> 64 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 64 Ala Pro Gly Pro Ser Ala Pro Ser His Arg Ser Leu Pro Ser Arg Ala 1 5 10 15 Phe Gly <210> 65 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 65 Pro Arg Asn Ser Ile His Phe Leu His Pro Leu Leu Val Ala Pro Leu 1 5 10 15 Gly Ala <210> 66 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 66 Met Pro Ser Leu Ser Gly Val Leu Gln Val Arg Tyr Leu Ser Pro Pro 1 5 10 15 Asp Leu <210> 67 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 67 Ser Pro Gln Tyr Pro Ser Pro Leu Thr Leu Thr Leu Pro Pro His Pro 1 5 10 15 Ser Leu <210> 68 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 68 Asn Pro Ser Leu Asn Pro Pro Ser Tyr Leu His Arg Ala Pro Ser Arg 1 5 10 15 Ile Ser <210> 69 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 69 Leu Pro Trp Arg Thr Ser Leu Leu Pro Ser Leu Pro Leu Arg Arg Arg 1 5 10 15 Pro <210> 70 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 70 Pro Pro Leu Phe Ala Lys Gly Pro Val Gly Leu Leu Ser Arg Ser Phe 1 5 10 15 Pro Pro <210> 71 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 71 Val Pro Pro Ala Pro Val Val Ser Leu Arg Ser Ala His Ala Arg Pro 1 5 10 15 Pro Tyr <210> 72 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 72 Leu Arg Pro Thr Pro Pro Arg Val Arg Ser Tyr Thr Cys Cys Pro Thr 1 5 10 15 Pro <210> 73 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 73 Pro Asn Val Ala His Val Leu Pro Leu Leu Thr Val Pro Trp Asp Asn 1 5 10 15 Leu Arg <210> 74 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> FLEXIBLE LINKER SEQUENCE <400> 74 Cys Asn Pro Leu Leu Pro Leu Cys Ala Arg Ser Pro Ala Val Arg Thr 1 5 10 15 Phe Pro <210> 75 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Rigid linker sequence <400> 75 Gly Ala Pro Ala Pro Ala Ala Pro Ala Pro Ala 1 5 10 <210> 76 <211> 4 <212> PRT <213> Artificial Sequence <220> <223> Rigid linker sequence <400> 76 Pro Pro Pro Pro One <210> 77 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LINKER SEQUENCE <400> 77 Asp Leu Cys Leu Arg Asp Trp Gly Cys Leu Trp 1 5 10 <210> 78 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LINKER SEQUENCE <400> 78 Asp Ile Cys Leu Pro Arg Trp Gly Cys Leu Trp 1 5 10 <210> 79 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> LINKER SEQUENCE <400> 79 Met Glu Asp Ile Cys Leu Pro Arg Trp Gly Cys Leu Trp Gly Asp 1 5 10 15 <210> 80 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> LINKER SEQUENCE <400> 80 Gln Arg Leu Met Glu Asp Ile Cys Leu Pro Arg Trp Gly Cys Leu Trp 1 5 10 15 Glu Asp Asp Glu 20 <210> 81 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> LINKER SEQUENCE <400> 81 Gln Gly Leu Ile Gly Asp Ile Cys Leu Pro Arg Trp Gly Cys Leu Trp 1 5 10 15 Gly Arg Ser Val 20 <210> 82 <211> 21 <212> PRT <213> Artificial Sequence <220> <223> LINKER SEQUENCE <400> 82 Gln Gly Leu Ile Gly Asp Ile Cys Leu Pro Arg Trp Gly Cys Leu Trp 1 5 10 15 Gly Arg Ser Val Lys 20 <210> 83 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> LINKER SEQUENCE <400> 83 Glu Asp Ile Cys Leu Pro Arg Trp Gly Cys Leu Trp Glu Asp Asp 1 5 10 15 <210> 84 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> LINKER SEQUENCE <400> 84 Arg Leu Met Glu Asp Ile Cys Leu Pro Arg Trp Gly Cys Leu Trp Glu 1 5 10 15 Asp Asp <210> 85 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> LINKER SEQUENCE <400> 85 Met Glu Asp Ile Cys Leu Pro Arg Trp Gly Cys Leu Trp Glu Asp Asp 1 5 10 15 <210> 86 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> LINKER SEQUENCE <400> 86 Met Glu Asp Ile Cys Leu Pro Arg Trp Gly Cys Leu Trp Glu Asp 1 5 10 15 <210> 87 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> LINKER SEQUENCE <400> 87 Arg Leu Met Glu Asp Ile Cys Leu Ala Arg Trp Gly Cys Leu Trp Glu 1 5 10 15 Asp Asp <210> 88 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> LINKER SEQUENCE <400> 88 Glu Val Arg Ser Phe Cys Thr Arg Trp Pro Ala Glu Lys Ser Cys Lys 1 5 10 15 Pro Leu Arg Gly 20 <210> 89 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> LINKER SEQUENCE <400> 89 Arg Ala Pro Glu Ser Phe Val Cys Tyr Trp Glu Thr Ile Cys Phe Glu 1 5 10 15 Arg Ser Glu Gln 20 <210> 90 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LINKER SEQUENCE <400> 90 Glu Met Cys Tyr Phe Pro Gly Ile Cys Trp Met 1 5 10 <210> 91 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> PDGFR RECEPTOR A <400> 91 Ala Val Leu Val Leu Leu Val Ile Val Ile Ile Ser Leu Ile Val Leu 1 5 10 15 Val Val Ile Trp 20 <210> 92 <211> 21 <212> PRT <213> Artificial Sequence <220> <223> PDGFR RECEPTOR B <400> 92 Val Val Ile Ser Ala Ile Leu Ala Leu Val Val Leu Thr Ile Ile Ser 1 5 10 15 Leu Ile Ile Leu Ile 20 <210> 93 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> INSULIN-LIKE GROWTH FACTOR 1 <400> 93 Ile Ile Ile Gly Pro Pro Leu Ile Phe Val Phe Leu Phe Ser Val Val 1 5 10 15 Ile Gly Ser Ile Tyr Leu Phe Leu 20 <210> 94 <211> 28 <212> PRT <213> Artificial Sequence <220> <223> IL6-R <400> 94 Ser Ser Ser Val Pro Leu Pro Thr Phe Leu Val Ala Gly Gly Ser Leu 1 5 10 15 Ala Phe Gly Thr Leu Leu Cys Ile Ala Ile Val Leu 20 25 <210> 95 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> CD28 <400> 95 Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu 1 5 10 15 Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val 20 25 <210> 96 <211> 34522 <212> DNA <213> Artificial Sequence <220> <223> NG-348 virus genome sequence comprising a transgene cassette that encoding a membrane-anchored chimeric form an anti-human CD3e scFv, and CD80 inserted in the region BY <400> 96 tctatctata taatatacct tatagatgga atggtgccaa tatgtaaatg aggtgatttt 60 aaaaagtgtg gatcgtgtgg tgattggctg tggggttaac ggctaaaagg ggcggtgcga 120 ccgtgggaaa atgacgtttt gtgggggtgg agtttttttg caagttgtcg cgggaaatgt 180 gacgcataaa aaggcttttt tctcacggaa ctacttagtt ttcccacggt atttaacagg 240 aaatgaggta gttttgaccg gatgcaagtg aaaattgttg attttcgcgc gaaaactgaa 300 tgaggaagtg tttttctgaa taatgtggta tttatggcag ggtggagtat ttgttcaggg 360 ccaggtagac tttgacccat tacgtggagg tttcgattac cgtgtttttt acctgaattt 420 ccgcgtaccg tgtcaaagtc ttctgttttt acgtaggtgt cagctgatcg ctagggtatt 480 tatacctcag ggtttgtgtc aagaggccac tcttgagtgc cagcgagaag agttttctcc 540 tctgcgccgg cagtttaata ataaaaaaat gagagatttg cgatttctgc ctcaggaaat 600 aatctctgct gagactggaa atgaaatatt ggagcttgtg gtgcacgccc tgatgggaga 660 cgatccggag ccacctgtgc agctttttga gcctcctacg cttcaggaac tgtatgattt 720 agaggtagag ggatcggagg attctaatga ggaagctgta aatggctttt ttaccgattc 780 tatgctttta gctgctaatg aagggttaga attagatccg cctttggaca cttttgatac 840 tccaggggta attgtggaaa gcggtacagg tgtaagaaaa ttacctgatt tgagttccgt 900 ggactgtgat ttgcactgct atgaagacgg gtttcctccg agtgatgagg aggaccatga 960 aaaggagcag tccatgcaga ctgcagcggg tgagggagtg aaggctgcca atgttggttt 1020 tcagttggat tgcccggagc ttcctggaca tggctgtaag tcttgtgaat ttcacaggaa 1080 aaatactgga gtaaaggaac tgttatgttc gctttgttat atgagaacgc actgccactt 1140 tatttacagt aagtgtgttt aagttaaaat ttaaaggaat atgctgtttt tcacatgtat 1200 attgagtgtg agttttgtgc ttcttattat aggtcctgtg tctgatgctg atgaatcacc 1260 atctcctgat tctactacct cacctcctga gattcaagca cctgttcctg tggacgtgcg 1320 caagcccatt cctgtgaagc ttaagcctgg gaaacgtcca gcagtggaaa aacttgagga 1380 cttgttacag ggtggggacg gacctttgga cttgagtaca cggaaacgtc caagacaata 1440 agtgttccat atccgtgttt acttaaggtg acgtcaatat ttgtgtgaca gtgcaatgta 1500 ataaaaatat gttaactgtt cactggtttt tattgctttt tgggcgggga ctcaggtata 1560 taagtagaag cagacctgtg tggttagctc ataggagctg gctttcatcc atggaggttt 1620 gggccatttt ggaagacctt aggaagacta ggcaactgtt agagaacgct tcggacggag 1680 tctccggttt ttggagattc tggttcgcta gtgaattagc tagggtagtt tttaggataa 1740 aacaggacta taaacaagaa tttgaaaagt tgttggtaga ttgcccagga ctttttgaag 1800 ctcttaattt gggccatcag gttcacttta aagaaaaagt tttatcagtt ttagactttt 1860 caaccccagg tagaactgct gctgctgtgg cttttcttac ttttatatta gataaatgga 1920 tcccgcagac tcatttcagc aggggatacg ttttggattt catagccaca gcattgtgga 1980 gaacatggaa ggttcgcaag atgaggacaa tcttaggtta ctggccagtg cagcctttgg 2040 gtgtagcggg aatcctgagg catccaccgg tcatgccagc ggttctggag gaggaacagc 2100 aagaggacaa cccgagagcc ggcctggacc ctccagtgga ggaggcggag tagctgactt 2160 gtctcctgaa ctgcaacggg tgcttactgg atctacgtcc actggacggg ataggggcgt 2220 taagagggag agggcatcta gtggtactga tgctagatct gagttggctt taagtttaat 2280 gagtcgcaga cgtcctgaaa ccatttggtg gcatgaggtt cagaaagagg gaagggatga 2340 agtttctgta ttgcaggaga aatattcact ggaacaggtg aaaacatgtt ggttggagcc 2400 tgaggatgat tgggaggtgg ccattaaaaa ttatgccaag atagctttga ggcctgataa 2460 acagtataag attactagac ggattaatat ccggaatgct tgttacatat ctggaaatgg 2520 ggctgaggtg gtaatagata ctcaagacaa ggcagttatt agatgctgca tgatggatat 2580 gtggcctggg gtagtcggta tggaagcagt aacttttgta aatgttaagt ttaggggaga 2640 tggttataat ggaatagtgt ttatggccaa taccaaactt atattgcatg gttgtagctt 2700 ttttggtttc aacaatacct gtgtagatgc ctggggacag gttagtgtac ggggatgtag 2760 tttctatgcg tgttggattg ccacagctgg cagaaccaag agtcaattgt ctctgaagaa 2820 atgcatattt caaagatgta acctgggcat tctgaatgaa ggcgaagcaa gggtccgcca 2880 ctgcgcttct acagatactg gatgttttat tttgattaag ggaaatgcca gcgtaaagca 2940 taacatgatt tgcggtgctt ccgatgagag gccttatcaa atgctcactt gtgctggtgg 3000 gcattgtaat atgctggcta ctgtgcatat tgtttcccat caacgcaaaa aatggcctgt 3060 ttttgatcac aatgtgatga cgaagtgtac catgcatgca ggtgggcgta gaggaatgtt 3120 tatgccttac cagtgtaaca tgaatcatgt gaaagtgttg ttggaaccag atgccttttc 3180 cagaatgagc ctaacaggaa tttttgacat gaacatgcaa atctggaaga tcctgaggta 3240 tgatgatacg agatcgaggg tacgcgcatg cgaatgcgga ggcaagcatg ccaggttcca 3300 gccggtgtgt gtagatgtga ctgaagatct cagaccggat catttggtta ttgcccgcac 3360 tggagcagag ttcggatcca gtggagaaga aactgactaa ggtgagtatt gggaaaactt 3420 tggggtggga ttttcagatg gacagattga gtaaaaattt gttttttctg tcttgcagct 3480 gtcatgagtg gaaacgcttc ttttaagggg ggagtcttca gcccttatct gacagggcgt 3540 ctcccatcct gggcaggagt tcgtcagaat gttatgggat ctactgtgga tggaagaccc 3600 gtccaacccg ccaattcttc aacgctgacc tatgctactt taagttcttc acctttggac 3660 gcagctgcag ctgccgccgc cgcttctgtt gccgctaaca ctgtgcttgg aatgggttac 3720 tatggaagca tcatggctaa ttccacttcc tctaataacc cttctaccct gactcaggac 3780 aagttacttg tccttttggc ccagctggag gctttgaccc aacgtctggg tgaactttct 3840 cagcaggtgg tcgagttgcg agtacaaact gagtctgctg tcggcacggc aaagtctaaa 3900 taaaaaaatc ccagaatcaa tgaataaata aacaagcttg ttgttgattt aaaatcaagt 3960 gtttttattt catttttcgc gcacggtatg ccctagacca ccgatctcta tcattgagaa 4020 ctcggtggat tttttccagg atcctataga ggtgggattg aatgtttaga tacatgggca 4080 ttaggccgtc tttggggtgg agatagctcc attgaaggga ttcatgctcc ggggtagtgt 4140 tgtaaatcac ccagtcataa caaggtcgca gtgcatggtg ttgcacaata tcttttagaa 4200 gtaggctgat tgccacagat aagcccttgg tgtaggtgtt tacaaaccgg ttgagctggg 4260 atgggtgcat tcggggtgaa attatgtgca ttttggattg gatttttaag ttggcaatat 4320 tgccgccaag atcccgtctt gggttcatgt tatgaaggac caccaagacg gtgtatccgg 4380 tacatttagg aaatttatcg tgcagcttgg atggaaaagc gtggaaaaat ttggagacac 4440 ccttgtgtcc tccaagattt tccatgcact catccatgat aatagcaatg gggccgtggg 4500 cagcggcgcg ggcaaacacg ttccgtgggt ctgacacatc atagttatgt tcctgagtta 4560 aatcatcata agccatttta atgaatttgg ggcggagagt accagattgg ggtatgaatg 4620 ttccttcggg ccccggagca tagttcccct cacagatttg catttcccaa gctttcagtt 4680 ccgagggtgg aatcatgtcc acctgggggg ctatgaaaaa caccgtttct ggggcggggg 4740 tgattaattg tgatgatagc aaatttctga gcaattgaga tttgccacat ccggtggggc 4800 cataaatgat tccgattacg ggttgcaggt ggtagtttag ggaacggcaa ctgccgtctt 4860 ctcgaagcaa gggggccacc tcgttcatca tttcccttac atgcatattt tcccgcacca 4920 aatccattag gaggcgctct cctcctagtg atagaagttc ttgtagtgag gaaaagtttt 4980 tcagcggttt cagaccgtca gccatgggca ttttggagag agtttgctgc aaaagttcta 5040 gtctgttcca cagttcagtg atgtgttcta tggcatctcg atccagcaga cctcctcgtt 5100 tcgcgggttt ggacggctcc tggaataggg tatgagacga tgggcgtcca gcgctgccag 5160 ggttcggtcc ttccagggtc tcagtgttcg agtcagggtt gtttccgtca cagtgaaggg 5220 gtgtgcgcct gcttgggcgc ttgccagggt gcgcttcaga ctcatcctgc tggtcgaaaa 5280 cttctgtcgc ttggcgccct gtatgtcggc caagtagcag tttaccatga gttcgtagtt 5340 gagcgcctcg gctgcgtggc ctttggcgcg gagcttacct ttggaagttt tcttgcatac 5400 cgggcagtat aggcatttca gcgcatacaa cttgggcgca aggaaaacgg attctgggga 5460 gtatgcatct gcgccgcagg aggcgcaaac agtttcacat tccaccagcc aggttaaatc 5520 cggttcattg gggtcaaaaa caagttttcc gccatatttt ttgatgcgtt tcttaccttt 5580 ggtctccatg agttcgtgtc ctcgttgagt gacaaacagg ctgtccgtgt ccccgtagac 5640 tgattttaca ggcctcttct ccagtggagt gcctcggtct tcttcgtaca ggaactctga 5700 ccactctgat acaaaggcgc gcgtccaggc cagcacaaag gaggctatgt gggaggggta 5760 gcgatcgttg tcaaccaggg ggtccacctt ttccaaagta tgcaaacaca tgtcaccctc 5820 ttcaacatcc aggaatgtga ttggcttgta ggtgtatttc acgtgacctg gggtccccgc 5880 tgggggggta taaaaggggg cggttctttg ctcttcctca ctgtcttccg gatcgctgtc 5940 caggaacgtc agctgttggg gtaggtattc cctctcgaag gcgggcatga cctctgcact 6000 caggttgtca gtttctaaga acgaggagga tttgatattg acagtgccgg ttgagatgcc 6060 tttcatgagg ttttcgtcca tctggtcaga aaacacaatt tttttattgt caagtttggt 6120 ggcaaatgat ccatacaggg cgttggataa aagtttggca atggatcgca tggtttggtt 6180 cttttccttg tccgcgcgct ctttggcggc gatgttgagt tggacatact cgcgtgccag 6240 gcacttccat tcggggaaga tagttgttaa ttcatctggc acgattctca cttgccaccc 6300 tcgattatgc aaggtaatta aatccacact ggtggccacc tcgcctcgaa ggggttcatt 6360 ggtccaacag agcctacctc ctttcctaga acagaaaggg ggaagtgggt ctagcataag 6420 ttcatcggga gggtctgcat ccatggtaaa gattcccgga agtaaatcct tatcaaaata 6480 gctgatggga gtggggtcat ctaaggccat ttgccattct cgagctgcca gtgcgcgctc 6540 atatgggtta aggggactgc cccatggcat gggatgggtg agtgcagagg catacatgcc 6600 acagatgtca tagacgtaga tgggatcctc aaagatgcct atgtaggttg gatagcatcg 6660 cccccctctg atacttgctc gcacatagtc atatagttca tgtgatggcg ctagcagccc 6720 cggacccaag ttggtgcgat tgggtttttc tgttctgtag acgatctggc gaaagatggc 6780 gtgagaattg gaagagatgg tgggtctttg aaaaatgttg aaatgggcat gaggtagacc 6840 tacagagtct ctgacaaagt gggcataaga ttcttgaagc ttggttacca gttcggcggt 6900 gacaagtacg tctagggcgc agtagtcaag tgtttcttga atgatgtcat aacctggttg 6960 gtttttcttt tcccacagtt cgcggttgag aaggtattct tcgcgatcct tccagtactc 7020 ttctagcgga aacccgtctt tgtctgcacg gtaagatcct agcatgtaga actgattaac 7080 tgccttgtaa gggcagcagc ccttctctac gggtagagag tatgcttgag cagcttttcg 7140 tagcgaagcg tgagtaaggg caaaggtgtc tctgaccatg actttgagga attggtattt 7200 gaagtcgatg tcgtcacagg ctccctgttc ccagagttgg aagtctaccc gtttcttgta 7260 ggcggggttg ggcaaagcga aagtaacatc attgaagaga atcttgccgg ccctgggcat 7320 gaaattgcga gtgatgcgaa aaggctgtgg tacttccgct cggttattga taacctgggc 7380 agctaggacg atctcgtcga aaccgttgat gttgtgtcct acgatgtata attctatgaa 7440 acgcggcgtg cctctgacgt gaggtagctt actgagctca tcaaaggtta ggtctgtggg 7500 gtcagataag gcgtagtgtt cgagagccca ttcgtgcagg tgaggattcg ctttaaggaa 7560 ggaggaccag aggtccactg ccagtgctgt ttgtaactgg tcccggtact gacgaaaatg 7620 ccgtccgact gccatttttt ctggggtgac gcaatagaag gtttgggggt cctgccgcca 7680 gcgatcccac ttgagtttta tggcgaggtc ataggcgatg ttgacgagcc gctggtctcc 7740 agagagtttc atgaccagca tgaaggggat tagctgcttg ccaaaggacc ccatccaggt 7800 gtaggtttcc acatcgtagg tgagaaagag cctttctgtg cgaggatgag agccaatcgg 7860 gaagaactgg atctcctgcc accagttgga ggaatggctg ttgatgtgat ggaagtagaa 7920 ctccctgcga cgcgccgagc attcatgctt gtgcttgtac agacggccgc agtagtcgca 7980 gcgttgcacg ggttgtatct cgtgaatgag ttgtacctgg cttcccttga cgagaaattt 8040 cagtgggaag ccgaggcctg gcgattgtat ctcgtgcttt actatgttgt ctgcatcggc 8100 ctgttcatct tctgtctcga tggtggtcat gctgacgagc cctcgcggga ggcaagtcca 8160 gacctcggcg cggcaggggc ggagctcgag gacgagagcg cgcaggctgg agctgtccag 8220 ggtcctgaga cgctgcggac tcaggttagt aggcagtgtc aggagattaa cttgcatgat 8280 cttttggagg gcgtgcggga ggttcagata gtacttgatc tcaacgggtc cgttggtgga 8340 gatgtcgatg gcttgcaggg ttccgtgtcc cttgggcgct accaccgtgc ccttgttttt 8400 cattttggac ggcggtggct ctgttgcttc ttgcatgttt agaagcggtg tcgagggcgc 8460 gcaccgggcg gcaggggcgg ctcgggaccc ggcggcatgg ctggcagtgg tacgtcggcg 8520 ccgcgcgcgg gtaggttctg gtactgcgcc ctgagaagac tcgcatgcgc gacgacgcgg 8580 cggttgacat cctggatctg acgcctctgg gtgaaagcta ccggccccgt gagcttgaac 8640 ctgaaagaga gttcaacaga atcaatctcg gtatcgttga cggcggcttg cctaaggatt 8700 tcttgcacgt caccagagtt gtcctggtag gcgatctccg ccatgaactg ctcgatctct 8760 tcctcttgaa gatctccgcg gcccgctctc tcgacggtgg ccgcgaggtc gttggagatg 8820 cgcccaatga gttgagagaa tgcattcatg cccgcctcgt tccagacgcg gctgtagacc 8880 acggccccca cgggatctct cgcgcgcatg accacctggg cgaggttgag ctccacgtgg 8940 cgggtgaaga ccgcatagtt gcataggcgc tggaaaaggt agttgagtgt ggtggcgatg 9000 tgctcggtga cgaagaaata catgatccat cgtctcagcg gcatctcgct gacatcgccc 9060 agagcttcca agcgctccat ggcctcgtag aagtccacgg caaaattaaa aaactgggag 9120 tttcgcgcgg acacggtcaa ctcctcttcc agaagacgga taagttcggc gatggtggtg 9180 cgcacctcgc gctcgaaagc ccctgggatt tcttcctcaa tctcttcttc ttccactaac 9240 atctcttcct cttcaggtgg ggctgcagga ggagggggaa cgcggcgacg ccggcggcgc 9300 acgggcagac ggtcgatgaa tctttcaatg acctctccgc ggcggcggcg catggtttca 9360 gtgacggcgc ggccgttctc gcgcggtcgc agagtaaaaa caccgccgcg catctcctta 9420 aagtggtgac tgggaggttc tccgtttggg agggagaggg cgctgattat acattttatt 9480 aattggcccg tagggactgc acgcagagat ctgatcgtgt caagatccac gggatctgaa 9540 aacctttcga cgaaagcgtc taaccagtca cagtcacaag gtaggctgag tacggcttct 9600 tgtgggcggg ggtggttatg tgttcggtct gggtcttctg tttcttcttc atctcgggaa 9660 ggtgagacga tgctgctggt gatgaaatta aagtaggcag ttctaagacg gcggatggtg 9720 gcgaggagca ccaggtcttt gggtccggct tgctggatac gcaggcgatt ggccattccc 9780 caagcattat cctgacatct agcaagatct ttgtagtagt cttgcatgag ccgttctacg 9840 ggcacttctt cctcacccgt tctgccatgc atacgtgtga gtccaaatcc gcgcattggt 9900 tgtaccagtg ccaagtcagc tacgactctt tcggcgagga tggcttgctg tacttgggta 9960 agggtggctt gaaagtcatc aaaatccaca aagcggtggt aagctcctgt attaatggtg 10020 taagcacagt tggccatgac tgaccagtta actgtctggt gaccagggcg cacgagctcg 10080 gtgtatttaa ggcgcgaata ggcgcgggtg tcaaagatgt aatcgttgca ggtgcgcacc 10140 agatactggt accctataag aaaatgcggc ggtggttggc ggtagagagg ccatcgttct 10200 gtagctggag cgccaggggc gaggtcttcc aacataaggc ggtgatagcc gtagatgtac 10260 ctggacatcc aggtgattcc tgcggcggta gtagaagccc gaggaaactc gcgtacgcgg 10320 ttccaaatgt tgcgtagcgg catgaagtag ttcattgtag gcacggtttg accagtgagg 10380 cgcgcgcagt cattgatgct ctatagacac ggagaaaatg aaagcgttca gcgactcgac 10440 tccgtagcct ggaggaacgt gaacgggttg ggtcgcggtg taccccggtt cgagacttgt 10500 actcgagccg gccggagccg cggctaacgt ggtattggca ctcccgtctc gacccagcct 10560 acaaaaatcc aggatacgga atcgagtcgt tttgctggtt tccgaatggc agggaagtga 10620 gtcctatttt ttttttttgc cgctcagatg catcccgtgc tgcgacagat gcgcccccaa 10680 caacagcccc cctcgcagca gcagcagcag caatcacaaa aggctgtccc tgcaactact 10740 gcaactgccg ccgtgagcgg tgcgggacag cccgcctatg atctggactt ggaagagggc 10800 gaaggactgg cacgtctagg tgcgccttca cccgagcggc atccgcgagt tcaactgaaa 10860 aaagattctc gcgaggcgta tgtgccccaa cagaacctat ttagagacag aagcggcgag 10920 gagccggagg agatgcgagc ttcccgcttt aacgcgggtc gtgagctgcg tcacggtttg 10980 gaccgaagac gagtgttgcg ggacgaggat ttcgaagttg atgaaatgac agggatcagt 11040 cctgccaggg cacacgtggc tgcagccaac cttgtatcgg cttacgagca gacagtaaag 11 100 gaagagcgta acttccaaaa gtcttttaat aatcatgtgc gaaccctgat tgcccgcgaa 11160 gaagttaccc ttggtttgat gcatttgtgg gatttgatgg aagctatcat tcagaaccct 11220 actagcaaac ctctgaccgc ccagctgttt ctggtggtgc aacacagcag agacaatgag 11280 gctttcagag aggcgctgct gaacatcacc gaacccgagg ggagatggtt gtatgatctt 11340 atcaacattc tacagagtat catagtgcag gagcggagcc tgggcctggc cgagaaggtg 11400 gctgccatca attactcggt tttgagcttg ggaaaatatt acgctcgcaa aatctacaag 11460 actccatacg ttcccataga caaggaggtg aagatagatg ggttctacat gcgcatgacg 11520 ctcaaggtct tgaccctgag cgatgatctt ggggtgtatc gcaatgacag aatgcatcgc 11580 gcggttagcg ccagcaggag gcgcgagtta agcgacaggg aactgatgca cagtttgcaa 11640 agagctctga ctggagctgg aaccgagggt gagaattact tcgacatggg agctgacttg 11700 cagtggcagc ctagtcgcag ggctctgagc gccgcgacgg caggatgtga gcttccttac 11760 atagaagagg cggatgaagg cgaggaggaa gagggcgagt acttggaaga ctgatggcac 11820 aacccgtgtt ttttgctaga tggaacagca agcaccggat cccgcaatgc gggcggcgct 11880 gcagagccag ccgtccggca ttaactcctc ggacgattgg acccaggcca tgcaacgtat 11940 catggcgttg acgactcgca accccgaagc ctttagacag caaccccagg ccaaccgtct 12000 atcggccatc atggaagctg tagtgccttc ccgctctaat cccactcatg agaaggtcct 12060 ggccatcgtg aacgcgttgg tggagaacaa agctattcgt ccagatgagg ccggactggt 12120 atacaacgct ctcttagaac gcgtggctcg ctacaacagt agcaatgtgc aaaccaattt 12180 ggaccgtatg ataacagatg tacgcgaagc cgtgtctcag cgcgaaaggt tccagcgtga 12240 tgccaacctg ggttcgctgg tggcgttaaa tgctttcttg agtactcagc ctgctaatgt 12300 gccgcgtggt caacaggatt atactaactt tttaagtgct ttgagactga tggtatcaga 12360 agtacctcag agcgaagtgt atcagtccgg tcctgattac ttctttcaga ctagcagaca 12420 gggcttgcag acggtaaatc tgagccaagc ttttaaaaac cttaaaggtt tgtggggagt 12480 gcatgccccg gtaggagaaa gagcaaccgt gtctagcttg ttaactccga actcccgcct 12540 attattactg ttggtagctc ctttcaccga cagcggtagc atcgaccgta attcctattt 12600 gggttaccta ctaaacctgt atcgcgaagc catagggcaa agtcaggtgg acgagcagac 12660 ctatcaagaa attacccaag tcagtcgcgc tttgggacag gaagacactg gcagtttgga 12720 agccactctg aacttcttgc ttaccaatcg gtctcaaaag atccctcctc aatatgctct 12780 tactgcggag gaggagagga tccttagata tgtgcagcag agcgtgggat tgtttctgat 12840 gcaagagggg gcaactccga ctgcagcact ggacatgaca gcgcgaaata tggagcccag 12900 catgtatgcc agtaaccgac ctttcattaa caaactgctg gactacttgc acagagctgc 12960 cgctatgaac tctgattatt tcaccaatgc catcttaaac ccgcactggc tgcccccacc 13020 tggtttctac acgggcgaat atgacatgcc cgaccctaat gacggatttc tgtgggacga 13080 cgtggacagc gatgtttttt cacctctttc tgatcatcgc acgtggaaaa aggaaggcgg 13140 cgatagaatg cattcttctg catcgctgtc cggggtcatg ggtgctaccg cggctgagcc 13200 cgagtctgca agtccttttc ctagtctacc cttttctcta cacagtgtac gtagcagcga 13260 agtgggtaga ataagtcgcc cgagtttaat gggcgaagag gagtatctaa acgattcctt 13320 gctcagaccg gcaagagaaa aaaatttccc aaacaatgga atagaaagtt tggtggataa 13380 aatgagtaga tggaagactt atgctcagga tcacagagac gagcctggga tcatggggat 13440 tacaagtaga gcgagccgta gacgccagcg ccatgacaga cagaggggtc ttgtgtggga 13500 cgatgaggat tcggccgatg atagcagcgt gctggacttg ggtgggagag gaaggggcaa 13560 cccgtttgct catttgcgcc ctcgcttggg tggtatgttg taaaaaaaaa taaaaaaaaa 13620 actcaccaag gccatggcga cgagcgtacg ttcgttcttc tttattatct gtgtctagta 13680 taatgaggcg agtcgtgcta ggcggagcgg tggtgtatcc ggagggtcct cctccttcgt 13740 acgagagcgt gatgcagcag cagcaggcga cggcggtgat gcaatcccca ctggaggctc 13800 cctttgtgcc tccgcgatac ctggcaccta cggagggcag aaacagcatt cgttattcgg 13860 aactggcacc tcagtacgat accaccaggt tgtatctggt ggacaacaag tcggcggaca 13920 ttgcttctct gaactatcag aatgaccaca gcaacttctt gaccacggtg gtgcaaaaca 13980 atgactttac ccctacggaa gccagcaccc agaccattaa ctttgatgaa cgatcgcggt 14040 ggggcggtca gctaaagacc atcatgcata ctaacatgcc aaacgtgaac gagtatatgt 14100 ttagtaacaa gttcaaagcg cgtgtgatgg tgtccagaaa acctcccgac ggtgctgcag 14160 ttggggatac ttatgatcac aagcaggata ttttgaaata tgagtggttc gagtttactt 14220 tgccagaagg caacttttca gttactatga ctattgattt gatgaacaat gccatcatag 14280 ataattactt gaaagtgggt agacagaatg gagtgcttga aagtgacatt ggtgttaagt 14340 tcgacaccag gaacttcaag ctgggatggg atcccgaaac caagttgatc atgcctggag 14400 tgtatacgta tgaagccttc catcctgaca ttgtcttact gcctggctgc ggagtggatt 14460 ttaccgagag tcgtttgagc aaccttcttg gtatcagaaa aaaacagcca tttcaagagg 14520 gttttaagat tttgtatgaa gatttagaag gtggtaatat tccggccctc ttggatgtag 14580 atgcctatga gaacagtaag aaagaacaaa aagccaaaat agaagctgct acagctgctg 14640 cagaagctaa ggcaaacata gttgccagcg actctacaag ggttgctaac gctggagagg 14700 tcagaggaga caattttgcg ccaacacctg ttccgactgc agaatcatta ttggccgatg 14760 tgtctgaagg aacggacgtg aaactcacta ttcaacctgt agaaaaagat agtaagaata 14820 gaagctataa tgtgttggaa gacaaaatca acacagccta tcgcagttgg tatctttcgt 14880 acaattatgg cgatcccgaa aaaggagtgc gttcctggac attgctcacc acctcagatg 14940 tcacctgcgg agcagagcag gtctactggt cgcttccaga catgatgaag gatcctgtca 15000 ctttccgctc cactagacaa gtcagtaact accctgtggt gggtgcagag cttatgcccg 15060 tcttctcaaa gagcttctac aacgaacaag ctgtgtactc ccagcagctc cgccagtcca 15120 cctcgcttac gcacgtcttc aaccgctttc ctgagaacca gattttaatc cgtccgccgg 15180 cgcccaccat taccaccgtc agtgaaaacg ttcctgctct cacagatcac gggaccctgc 15240 cgttgcgcag cagtatccgg ggagtccaac gtgtgaccgt tactgacgcc agacgccgca 15300 cctgtcccta cgtgtacaag gcactgggca tagtcgcacc gcgcgtcctt tcaagccgca 15360 ctttctaaaa aaaaaaaaaa tgtccattct tatctcgccc agtaataaca ccggttgggg 15420 tctgcgcgct ccaagcaaga tgtacggagg cgcacgcaaa cgttctaccc aacatcctgt 15480 ccgtgttcgc ggacattttc gcgctccatg gggcgccctc aagggccgca ctcgcgttcg 15540 aaccaccgtc gatgatgtaa tcgatcaggt ggttgccgac gcccgtaatt atactcctac 15600 tgcgcctaca tctactgtgg atgcagttat tgacagtgta gtggctgacg ctcgcaacta 15660 tgctcgacgt aagagccggc gaaggcgcat tgccagacgc caccgagcta ccactgccat 15720 gcgagccgca agagctctgc tacgaagagc tagacgcgtg gggcgaagag ccatgcttag 15780 ggcggccaga cgtgcagctt cgggcgccag cgccggcagg tcccgcaggc aagcagccgc 15840 tgtcgcagcg gcgactattg ccgacatggc ccaatcgcga agaggcaatg tatactgggt 15900 gcgtgacgct gccaccggtc aacgtgtacc cgtgcgcacc cgtccccctc gcacttagaa 15960 gatactgagc agtctccgat gttgtgtccc agcggcgagg atgtccaagc gcaaatacaa 16020 ggaagaaatg ctgcaggtta tcgcacctga agtctacggc caaccgttga aggatgaaaa 16080 aaaaccccgc aaaatcaagc gggttaaaaa ggacaaaaaa gaagaggaag atggcgatga 16140 tgggctggcg gagtttgtgc gcgagtttgc cccacggcga cgcgtgcaat ggcgtgggcg 16200 caaagttcga catgtgttga gacctggaac ttcggtggtc tttacacccg gcgagcgttc 16260 aagcgctact tttaagcgtt cctatgatga ggtgtacggg gatgatgata ttcttgagca 16320 ggcggctgac cgattaggcg agtttgctta tggcaagcgt agtagaataa cttccaagga 16380 tgagacagtg tcgataccct tggatcatgg aaatcccacc cctagtctta aaccggtcac 16440 tttgcagcaa gtgttacccg taactccgcg aacaggtgtt aaacgcgaag gtgaagattt 16500 gtatcccact atgcaactga tggtacccaa acgccagaag ttggaggacg ttttggagaa 16560 agtaaaagtg gatccagata ttcaacctga ggttaaagtg agacccatta agcaggtagc 16620 gcctggtctg ggggtacaaa ctgtagacat taagattccc actgaaagta tggaagtgca 16680 aactgaaccc gcaaagccta ctgccacctc cactgaagtg caaacggatc catggatgcc 16740 catgcctatt acaactgacg ccgccggtcc cactcgaaga tcccgacgaa agtacggtcc 16800 agcaagtctg ttgatgccca attatgttgt acacccatct attattccta ctcctggtta 16860 ccgaggcact cgctactatc gcagccgaaa cagtacctcc cgccgtcgcc gcaagacacc 16920 tgcaaatcgc agtcgtcgcc gtagacgcac aagcaaaccg actcccggcg ccctggtgcg 16980 gcaagtgtac cgcaatggta gtgcggaacc tttgacactg ccgcgtgcgc gttaccatcc 17040 gagtatcatc acttaatcaa tgttgccgct gcctccttgc agatatggcc ctcacttgtc 17100 gccttcgcgt tcccatcact ggttaccgag gaagaaactc gcgccgtaga agagggatgt 17160 tgggacgcgg aatgcgacgc tacaggcgac ggcgtgctat ccgcaagcaa ttgcggggtg 17220 gttttttacc agccttaatt ccaattatcg ctgctgcaat tggcgcgata ccaggcatag 17280 cttccgtggc ggttcaggcc tcgcaacgac attgacattg gaaaaaaacg tataaataaa 17340 aaaaaaaaaa tacaatggac tctgacactc ctggtcctgt gactatgttt tcttagagat 17400 ggaagacatc aatttttcat ccttggctcc gcgacacggc acgaagccgt acatgggcac 17460 ctggagcgac atcggcacga gccaactgaa cgggggcgcc ttcaattgga gcagtatctg 17520 gagcgggctt aaaaattttg gctcaaccat aaaaacatac gggaacaaag cttggaacag 17580 cagtacagga caggcgctta gaaataaact taaagaccag aacttccaac aaaaagtagt 17640 cgatgggata gcttccggca tcaatggagt ggtagatttg gctaaccagg ctgtgcagaa 17700 aaagataaac agtcgtttgg acccgccgcc agcaacccca ggtgaaatgc aagtggagga 17760 agaaattcct ccgccagaaa aacgaggcga caagcgtccg cgtcccgatt tggaagagac 17820 gctggtgacg cgcgtagatg aaccgccttc ttatgaggaa gcaacgaagc ttggaatgcc 17880 caccactaga ccgatagccc caatggccac cggggtgatg aaaccttctc agttgcatcg 17940 acccgtcacc ttggatttgc cccctccccc tgctgctact gctgtacccg cttctaagcc 18000 tgtcgctgcc ccgaaaccag tcgccgtagc caggtcacgt cccgggggcg ctcctcgtcc 18060 aaatgcgcac tggcaaaata ctctgaacag catcgtgggt ctaggcgtgc aaagtgtaaa 18 120 acgccgtcgc tgcttttaat taaatatgga gtagcgctta acttgcctat ctgtgtatat 18180 gtgtcattac acgccgtcac agcagcagag gaaaaaagga agaggtcgtg cgtcgacgct 18240 gagttacttt caagatggcc accccatcga tgctgcccca atgggcatac atgcacatcg 18300 ccggacagga tgcttcggag tacctgagtc cgggtctggt gcagttcgcc cgcgccacag 18360 acacctactt caatctggga aataagttta gaaatcccac cgtagcgccg acccacgatg 18420 tgaccaccga ccgtagccag cggctcatgt tgcgcttcgt gcccgttgac cgggaggaca 18480 atacatactc ttacaaagtg cggtacaccc tggccgtggg cgacaacaga gtgctggata 18540 tggccagcac gttctttgac attaggggtg tgttggacag aggtcccagt ttcaaaccct 18600 attctggtac ggcttacaac tccctggctc ctaaaggcgc tccaaataca tctcagtgga 18660 ttgcagaagg tgtaaaaaat acaactggtg aggaacacgt aacagaagag gaaaccaata 18720 ctactactta cacttttggc aatgctcctg taaaagctga agctgaaatt acaaaagaag 18780 gactcccagt aggtttggaa gtttcagatg aagaaagtaa accgatttat gctgataaaa 18840 catatcagcc agaacctcag ctgggagatg aaacttggac tgaccttgat ggaaaaaccg 18900 aaaagtatgg aggcagggct ctcaaacccg atactaagat gaaaccatgc tacgggtcct 18960 ttgccaaacc tactaatgtg aaaggcggtc aggcaaaaca aaaaacaacg gagcagccaa 19020 atcagaaagt cgaatatgat atcgacatgg agttttttga tgcggcatcg cagaaaacaa 19080 acttaagtcc taaaattgtc atgtatgcag aaaatgtaaa tttggaaact ccagacactc 19140 atgtagtgta caaacctgga acagaagaca caagttccga agctaatttg ggacaacaat 19200 ctatgcccaa cagacccaac tacattggct tcagagataa ctttattgga cttatgtact 19260 ataacagtac tggtaacatg ggggtgctgg ctggtcaagc gtctcagtta aatgcagtgg 19320 ttgacttgca ggacagaaac acagaacttt cttaccaact cttgcttgac tctctgggcg 19380 acagaaccag atactttagc atgtggaatc aggctgtgga cagttatgat cctgatgtac 19440 gtgttattga aaatcatggt gtggaagatg aacttcccaa ctactgtttt ccactggacg 19500 gcataggtgt tccaacaacc agttacaaat caatagttcc aaatggagac aatgcgccta 19560 attggaagga acctgaagta aatggaacaa gtgagatcgg acagggtaat ttgtttgcca 19620 tggaaattaa ccttcaagcc aatctatggc gaagtttcct ttattccaat gtggctctat 19680 atctcccaga ctcgtacaaa tacaccccgt ccaatgtcac tcttccagaa aacaaaaaca 19740 cctacgacta catgaacggg cgggtggtgc cgccatctct agtagacacc tatgtgaaca 19800 ttggtgccag gtggtctctg gatgccatgg acaatgtcaa cccattcaac caccaccgta 19860 acgctggctt gcgttaccga tccatgcttc tgggtaacgg acgttatgtg cctttccaca 19920 tacaagtgcc tcaaaaattc ttcgctgtta aaaacctgct gcttctccca ggctcctaca 19980 cttatgagtg gaactttagg aaggatgtga acatggttct acagagttcc ctcggtaacg 20040 acctgcgggt agatggcgcc agcatcagtt tcacgagcat caacctctat gctacttttt 20100 tccccatggc tcacaacacc gcttccaccc ttgaagccat gctgcggaat gacaccaatg 20160 atcagtcatt caacgactac ctatctgcag ctaacatgct ctaccccatt cctgccaatg 20220 caaccaatat tcccatttcc attccttctc gcaactgggc ggctttcaga ggctggtcat 20280 ttaccagact gaaaaccaaa gaaactccct ctttggggtc tggatttgac ccctactttg 20340 tctattctgg ttctattccc tacctggatg gtaccttcta cctgaaccac acttttaaga 20400 aggtttccat catgtttgac tcttcagtga gctggcctgg aaatgacagg ttactatctc 20460 ctaacgaatt tgaaataaag cgcactgtgg atggcgaagg ctacaacgta gcccaatgca 20520 acatgaccaa agactggttc ttggtacaga tgctcgccaa ctacaacatc ggctatcagg 20580 gcttctacat tccagaagga tacaaagatc gcatgtattc atttttcaga aacttccagc 20640 ccatgagcag gcaggtggtt gatgaggtca attacaaaga cttcaaggcc gtcgccatac 20700 cctaccaaca caacaactct ggctttgtgg gttacatggc tccgaccatg cgccaaggtc 20760 aaccctatcc cgctaactat ccctatccac tcattggaac aactgccgta aatagtgtta 20820 cgcagaaaaa gttcttgtgt gacagaacca tgtggcgcat accgttctcg agcaacttca 20880 tgtctatggg ggcccttaca gacttgggac agaatatgct ctatgccaac tcagctcatg 20940 ctctggacat gacctttgag gtggatccca tggatgagcc caccctgctt tatcttctct 21000 tcgaagtttt cgacgtggtc agagtgcatc agccacaccg cggcatcatc gaggcagtct 21060 acctgcgtac accgttctcg gccggtaacg ctaccacgta agaagcttct tgcttcttgc 21120 aaatagcagc tgcaaccatg gcctgcggat cccaaaacgg ctccagcgag caagagctca 21180 gagccattgt ccaagacctg ggttgcggac cctatttttt gggaacctac gataagcgct 21240 tcccggggtt catggccccc gataagctcg cctgtgccat tgtaaatacg gccggacgtg 21300 agacgggggg agagcactgg ttggctttcg gttggaaccc acgttctaac acctgctacc 21360 tttttgatcc ttttggattc tcggatgatc gtctcaaaca gatttaccag tttgaatatg 21420 agggtctcct gcgccgcagc gctcttgcta ccaaggaccg ctgtattacg ctggaaaaat 21480 ctacccagac cgtgcagggt ccccgttctg ccgcctgcgg acttttctgc tgcatgttcc 21540 ttcacgcctt tgtgcactgg cctgaccgtc ccatggacgg aaaccccacc atgaaattgc 21600 taactggagt gccaaacaac atgcttcatt ctcctaaagt ccagcccacc ctgtgtgaca 21660 atcaaaaagc actctaccat tttcttaata cccattcgcc ttattttcgc tcccatcgta 21720 cacacatcga aagggccact gcgttcgacc gtatggatgt tcaataatga ctcatgtaaa 21780 caacgtgttc aataaacatc actttatttt tttacatgta tcaaggctct gcattactta 21840 tttatttaca agtcgaatgg gttctgacga gaatcagaat gacccgcagg cagtgatacg 21900 ttgcggaact gatacttggg ttgccacttg aattcgggaa tcaccaactt gggaaccggt 21960 atatcgggca ggatgtcact ccacagcttt ctggtcagct gcaaagctcc aagcaggtca 22020 ggagccgaaa tcttgaaatc acaattagga ccagtgcttt gagcgcgaga gttgcggtac 22080 accggattgc agcactgaaa caccatcagc gacggatgtc tcacgcttgc cagcacggtg 22140 ggatctgcaa tcatgcccac atccagatct tcagcattgg caatgctgaa cggggtcatc 22200 ttgcaggtct gcctacccat ggcgggcacc caattaggct tgtggttgca atcgcagtgc 22260 agggggatca gtatcatctt ggcctgatcc tgtctgattc ctggatacac ggctctcatg 22320 aaagcatcat attgcttgaa agcctgctgg gctttactac cctcggtata aaacatcccg 22380 caggacctgc tcgaaaactg gttagctgca cagccggcat cattcacaca gcagcgggcg 22440 tcattgttag ctatttgcac cacacttctg ccccagcggt tttgggtgat tttggttcgc 22500 tcgggattct cctttaaggc tcgttgtccg ttctcgctgg ccacatccat ctcgataatc 22560 tgctccttct gaatcataat attgccatgc aggcacttca gcttgccctc ataatcattg 22620 cagccatgag gccacaacgc acagcctgta cattcccaat tatggtgggc gatctgagaa 22680 aaagaatgta tcattccctg cagaaatctt cccatcatcg tgctcagtgt cttgtgacta 22740 gtgaaagtta actggatgcc tcggtgctcc tcgtttacgt actggtgaca gatgcgcttg 22800 tattgttcgt gttgctcagg cattagttta aaagaggttc taagttcgtt atccagcctg 22860 tacttctcca tcagcagaca catcacttcc atgcctttct cccaagcaga caccaggggc 22920 aagctaatcg gattcttaac agtgcaggca gcagctcctt tagccagagg gtcatcttta 22980 gcgatcttct caatgcttct tttgccatcc ttctcaacga tgcgcacggg cgggtagctg 23040 aaacccactg ctacaagttg cgcctcttct ctttcttctt cgctgtcttg actgatgtct 23100 tgcatgggga tatgtttggt cttccttggc ttctttttgg ggggtatcgg aggaggagga 23160 ctgtcgctcc gttccggaga cagggaggat tgtgacgttt cgctcaccat taccaactga 23220 ctgtcggtag aagaacctga ccccacacgg cgacaggtgt ttctcttcgg gggcagaggt 23280 ggaggcgatt gcgaagggct gcggtccgac ctggaaggcg gatgactggc agaacccctt 23340 ccgcgttcgg gggtgtgctc cctgtggcgg tcgcttaact gatttccttc gcggctggcc 23400 attgtgttct cctaggcaga gaaacaacag acatggaaac tcagccattg ctgtcaacat 23460 cgccacgagt gccatcacat ctcgtcctca gcgacgagga aaaggagcag agcttaagca 23520 ttccaccgcc cagtcctgcc accacctcta ccctagaaga taaggaggtc gacgcatctc 23580 atgacatgca gaataaaaaa gcgaaagagt ctgagacaga catcgagcaa gacccgggct 23640 atgtgacacc ggtggaacac gaggaagagt tgaaacgctt tctagagaga gaggatgaaa 23700 actgcccaaa acaacgagca gataactatc accaagatgc tggaaatagg gatcagaaca 23760 ccgactacct catagggctt gacggggaag acgcgctcct taaacatcta gcaagacagt 23820 cgctcatagt caaggatgca ttattggaca gaactgaagt gcccatcagt gtggaagagc 23880 tcagccgcgc ctacgagctt aacctctttt cacctcgtac tccccccaaa cgtcagccaa 23940 acggcacctg cgagccaaat cctcgcttaa acttttatcc agcttttgct gtgccagaag 24000 tactggctac ctatcacatc ttttttaaaa atcaaaaaat tccagtctcc tgccgcgcta 24060 atcgcacccg cgccgatgcc ctactcaatc tgggacctgg ttcacgctta cctgatatag 24120 cttccttgga agaggttcca aagatcttcg agggtctggg caataatgag actcgggccg 24180 caaatgctct gcaaaaggga gaaaatggca tggatgagca tcacagcgtt ctggtggaat 24 240 tggaaggcga taatgccaga ctcgcagtac tcaagcgaag catcgaggtc acacacttcg 24300 catatcccgc tgtcaacctg ccccctaaag tcatgacggc ggtcatggac cagttactca 24360 ttaagcgcgc aagtcccctt tcagaagaca tgcatgaccc agatgcctgt gatgagggta 24420 aaccagtggt cagtgatgag cagctaaccc gatggctggg caccgactct cccagggatt 24480 tggaagagcg tcgcaagctt atgatggccg tggtgctggt taccgtagaa ctagagtgtc 24540 tccgacgttt ctttaccgat tcagaaacct tgcgcaaact cgaagagaat ctgcactaca 24600 cttttagaca cggctttgtg cggcaggcat gcaagatatc taacgtggaa ctcaccaacc 24660 tggtttccta catgggtatt ctgcatgaga atcgcctagg acaaagcgtg ctgcacagca 24720 ccctgaaggg ggaagcccgc cgtgattaca tccgcgattg tgtctatctg tacctgtgcc 24780 acacgtggca aaccggcatg ggtgtatggc agcaatgttt agaagaacag aacttgaaag 24840 agcttgacaa gctcttacag aaatctctta aggttctgtg gacagggttc gacgagcgca 24900 ccgtcgcttc cgacctggca gacctcatct tcccagagcg tctcagggtt actttgcgaa 24960 acggattgcc tgactttatg agccagagca tgcttaacaa ttttcgctct ttcatcctgg 25020 aacgctccgg tatcctgccc gccacctgct gcgcactgcc ctccgacttt gtgcctctca 25080 cctaccgcga gtgccccccg ccgctatgga gtcactgcta cctgttccgt ctggccaact 25 140 atctctccta ccactcggat gtgatcgagg atgtgagcgg agacggcttg ctggagtgtc 25200 actgccgctg caatctgtgc acgccccacc ggtccctagc ttgcaacccc cagttgatga 25260 gcgaaaccca gataataggc acctttgaat tgcaaggccc cagcagccaa ggcgatgggt 25320 cttctcctgg gcaaagttta aaactgaccc cgggactgtg gacctccgcc tacttgcgca 25380 agtttgctcc ggaagattac cacccctatg aaatcaagtt ctatgaggac caatcacagc 25440 ctccaaaggc cgaactttcg gcctgcgtca tcacccaggg ggcaattctg gcccaattgc 25500 aagccatcca aaaatcccgc caagaatttc tactgaaaaa gggtaagggg gtctaccttg 25560 acccccagac cggcgaggaa ctcaacacaa ggttccctca ggatgtccca acgacgagaa 25620 aacaagaagt tgaaggtgca gccgccgccc ccagaagata tggaggaaga ttgggacagt 25680 caggcagagg aggcggagga ggacagtctg gaggacagtc tggaggaaga cagtttggag 25740 gaggaaaacg aggaggcaga ggaggtggaa gaagtaaccg ccgacaaaca gttatcctcg 25800 gctgcggaga caagcaacag cgctaccatc tccgctccga gtcgaggaac ccggcggcgt 25860 cccagcagta gatgggacga gaccggacgc ttcccgaacc caaccagcgc ttccaagacc 25920 ggtaagaagg atcggcaggg atacaagtcc tggcgggggc ataagaatgc catcatctcc 25980 tgcttgcatg agtgcggggg caacatatcc ttcacgcggc gctacttgct attccaccat 26040 ggggtgaact ttccgcgcaa tgttttgcat tactaccgtc acctccacag cccctactat 26100 agccagcaaa tcccggcagt ctcgacagat aaagacagcg gcggcgacct ccaacagaaa 26160 accagcagcg gcagttagaa aatacacaac aagtgcagca acaggaggat taaagattac 26220 agccaacgag ccagcgcaaa cccgagagtt aagaaatcgg atctttccaa ccctgtatgc 26280 catcttccag cagagtcggg gtcaagagca ggaactgaaa ataaaaaacc gatctctgcg 26340 ttcgctcacc agaagttgtt tgtatcacaa gagcgaagat caacttcagc gcactctcga 26400 ggacgccgag gctctcttca acaagtactg cgcgctgact cttaaagagt aggcagcgac 26460 cgcgcttatt caaaaaaggc gggaattaca tcatcctcga catgagtaaa gaaattccca 26520 cgccttacat gtggagttat caaccccaaa tgggattggc ggcaggcgcc tcccaggact 26580 actccacccg catgaattgg ctcagcgccg ggccttctat gatttctcga gttaatgata 26640 tacgcgccta ccgaaaccaa atacttttgg aacagtcagc tcttaccacc acgccccgcc 26700 aacaccttaa tcccagaaat tggcccgccg ccctagtgta ccaggaaagt cccgctccca 26760 ccactgtatt acttcctcga gacgcccagg ccgaagtcca aatgactaat gcaggtgcgc 26820 agttagctgg cggctccacc ctatgtcgtc acaggcctcg gcataatata aaacgcctga 26880 tgatcagagg ccgaggtatc cagctcaacg acgagtcggt gagctctccg cttggtctac 26940 gaccagacgg aatctttcag attgccggct gcgggagatc ttccttcacc cctcgtcagg 27000 ctgttctgac tttggaaagt tcgtcttcgc aaccccgctc gggcggaatc gggaccgttc 27060 aatttgtgga ggagtttact ccctctgtct acttcaaccc cttctccgga tctcctgggc 27120 attacccgga cgagttcata ccgaacttcg acgcgattag cgagtcagtg gacggctacg 27180 attgatgtct ggtgacgcgg ctgagctatc tcggctgcga catctagacc actgccgccg 27240 ctttcgctgc tttgcccggg aactcattga gttcatctac ttcgaactcc ccaaggatca 27300 ccctcaaggt ccggcccacg gagtgcggat ttctatcgaa ggcaaaatag actctcgcct 27360 gcaacgaatt ttctcccagc ggcccgtgct gatcgagcga gaccagggaa acaccacggt 27420 ttccatctac tgcatttgta atcaccccgg attgcatgaa agcctttgct gtcttatgtg 27480 tactgagttt aataaaaact gaattaagac tctcctacgg actgccgctt cttcaacccg 27540 gattttacaa ccagaagaac gaaacttttc ctgtcgtcca ggactctgtt aacttcacct 27600 ttcctactca caaactagaa gctcaacgac tacaccgctt ttccagaagc attttcccta 27660 ctaatactac tttcaaaacc ggaggtgagc tccaaggtct tcctacagaa aacccttggg 27720 tggaagcggg ccttgtagtg ctaggaattc ttgcgggtgg gcttgtgatt attctttgct 27780 acctatacac accttgcttc actttcttag tggtgttgtg gtattggttt aaaaaatggg 27840 gcccatacta gtcttgcttg ttttactttc gcttttggaa ccgggttctg ccaattacga 27900 tccatgtcta gacttcgacc cagaaaactg cacacttact tttgcacccg acacaagccg 27960 catctgtgga gttcatcgcc tctcttacga acttggcccc caacgacaaa aatttacctg 28020 catggtggga atcaacccca tagttatcac ccagcaaagt ggagatacta agggttgcat 28080 tcactgctcc tgcgattcca tcgagtgcac ctacaccctg ctgaagaccc tatgcggcct 28140 aagagacctg ctaccaatga attaaaaaat gattaataaa aaatcactta cttgaaatca 28200 gcaataaggt ctctgttgaa attttctccc agcagcacct cacttccctc ttcccaactc 28260 tggtattcta aaccccgttc agcggcatac tttctccata ctttaaaggg gatgtcaaat 28320 tttagctcct ctcctgtacc cacaatcttc atgtctttct tcccagatga ccaagagagt 28380 ccggctcagt gactccttca accctgtcta cccctatgaa gatgaaagca cctcccaaca 28440 cccctttata aacccagggt ttatttcccc aaatggcttc acacaaagcc caaacggagt 28500 tcttacttta aaatgtttaa ccccactaac aaccacaggc ggatctctac agctaaaagt 28560 gggaggggga cttacagtgg atgacaccaa cggttttttg aaagaaaaca taagtgccac 28620 cacaccactc gttaagactg gtcactctat aggtttacca ctaggagccg gattgggaac 28680 gaatgaaaat aaactttgta tcaaattagg acaaggactt acattcaatt caaacaacat 28740 ttgcattgat gacaatatta acaccttatg gacaggagtc aaccccaccg aagccaactg 28800 tcaaatcatg aactccagtg aatctaatga ttgcaaatta attctaacac tagttaaaac 28860 tggagcacta gtcactgcat ttgtttatgt tataggagta tctaacaatt ttaatatgct 28920 aactacacac agaaatataa attttactgc agagctgttt ttcgattcta ctggtaattt 28980 actaactaga ctctcatccc tcaaaactcc acttaatcat aaatcaggac aaaacatggc 29040 tactggtgcc attactaatg ctaaaggttt catgcccagc acgactgcct atcctttcaa 29100 tgataattct agagaaaaag aaaactacat ttacggaact tgttactaca cagctagtga 29160 tcgcactgct tttcccattg acatatctgt catgcttaac cgaagagcaa taaatgacga 29220 gacatcatat tgtattcgta taacttggtc ctggaacaca ggagatgccc cagaggtgca 29280 aacctctgct acaaccctag tcacctcccc atttaccttt tactacatca gagaagacga 29340 ctgacaaata aagtttgcga tcgccaggcc caccatggga tggagctgta tcatcctctt 29400 cttggtagca acagctacag gtgtccactc ccaggtgcag ctgcagcagt ctggggctga 29460 actggcaaga cctggggcct cagtgaagat gtcctgcaag gcttctggct acacctttac 29520 taggtacacg atgcactggg taaaacagag gcctggacag ggtctggaat ggattggata 29580 cattaatcct agccgtggtt atactaatta caatcagaag ttcaaggaca aggccacatt 29640 gactacagac aaatcctcca gcacagccta catgcaactg agcagcctga catctgagga 29700 ctctgcagtc tattactgtg caagatatta tgatgatcat tactgccttg actactgggg 29760 ccaaggcacc actctcacag tctcctcagg tggcggtggc tcgggcggtg gtggatctgg 29820 tggcggcgga tctgatatcg tgctcactca gtctccagca atcatgtctg catctccagg 29880 ggagaaggtc accatgacct gcagtgccag ctcaagtgta agttacatga actggtacca 29940 gcagaagtca ggcacctccc ccaaaagatg gatttatgac acatccaaac tggcttctgg 30000 agtccctgct cacttcaggg gcagtgggtc tgggacctct tactctctca caatcagcgg 30060 catggaggct gaagatgctg ccacttatta ctgccagcag tggagtagta acccattcac 30120 gttcggctcg gggacaaagt tggaaataaa ccggggatcc gaacaaaaac tcatctcaga 30180 agaggatctg aatgctgtgg gccaggacac gcaggaggtc atcgtggtgc cacactcctt 30240 gccctttaag gtggtggtga tctcagccat cctggccctg gtggtgctca ccatcatctc 30300 ccttatcatc ctcatcatgc tttggcagaa gaagccacgt ggaagcggag ctactaactt 30360 cagcctgctg aagcaggctg gagacgtgga ggagaaccct ggacctggcc acacacggag 30420 gcagggaaca tcaccatcca agtgtccata cctcaatttc tttcagctct tggtgctggc 30480 tggtctttct cacttctgtt caggtgttat ccacgtgacc aaggaagtga aagaagtggc 30540 aacgctgtcc tgtggtcaca atgtttctgt tgaagagctg gcacaaactc gcatctactg 30600 gcaaaaggag aagaaaatgg tgctgactat gatgtctggg gacatgaata tatggcccga 30660 gtacaagaac cggaccatct ttgatatcac taataacctc tccattgtga tcctggctct 30720 gcgcccatct gacgagggca catacgagtg tgttgttctg aagtatgaaa aagacgcttt 30780 caagcgggaa cacctggctg aagtgacgtt atcagtcaaa gctgacttcc ctacacctag 30840 tatatctgac tttgaaattc caacttctaa tattagaagg ataatttgct caacctctgg 30900 aggttttcca gagcctcacc tctcctggtt ggaaaatgga gaagaattaa atgccatcaa 30960 cacaacagtt tcccaagatc ctgaaactga gctctatgct gttagcagca aactggattt 31020 caatatgaca accaaccaca gcttcatgtg tctcatcaag tatggacatt taagagtgaa 31080 tcagaccttc aactggaata caaccaagca agagcatttt cctgataacc tgctcccatc 31140 ctgggccatt accttaatct cagtaaatgg aatttttgtg atatgctgcc tgacctactg 31200 ctttgcccca agatgcagag agagaaggag gaatgagaga ttgagaaggg aaagtgtacg 31260 ccctgtataa gctagcttga ctgactgaga tacagcgtac cttcagctca cagacatgat 31320 aagatacatt gatgagtttg gacaaaccac aactagaatg cagtgaaaaa aatgctttat 31380 ttgtgaaatt tgtgatgcta ttgctttatt tgtaaccatt ataagctgca ataaacaagt 31440 taacaacaac aattgcattc attttatgtt tcaggttcag ggggaggtgt gggaggtttt 31500 ttaaagcaag taaaacctct acaaatgtgg tagtcgtcag ctatcctgca ggaacttgtt 31560 tatttgaaaa tcaattcaca aaatccgagt agttattttg cctccccctt cccatttaac 31620 agaatacacc aatctctccc cacgcacagc tttaaacatt tggataccat tagatataga 31680 catggtttta gattccacat tccaaacagt ttcagagcga gccaatctgg ggtcagtgat 31740 agataaaaat ccatcgggat agtcttttaa agcgctttca cagtccaact gctgcggatg 31800 cgactccgga gtctggatca cggtcatctg gaagaagaac gatgggaatc ataatccgaa 31860 aacggtatcg gacgattgtg tctcatcaaa cccacaagca gccgctgtct gcgtcgctcc 31920 gtgcgactgc tgtttatggg atcagggtcc acagtgtcct gaagcatgat tttaatagcc 31980 cttaacatca actttctggt gcgatgcgcg cagcaacgca ttctgatttc actcaaatct 32040 ttgcagtagg tacaacacat tattacaata ttgtttaata aaccataatt aaaagcgctc 32 100 cagccaaaac tcatatctga tataatcgcc cctgcatgac catcatacca aagtttaata 32160 taaattaaat gacgttccct caaaaacaca ctacccacat acatgatctc ttttggcatg 32220 tgcatattaa caatctgtct gtaccatgga caacgttggt taatcatgca acccaatata 32280 accttccgga accacactgc caacaccgct cccccagcca tgcattgaag tgaaccctgc 32340 tgattacaat gacaatgaag aacccaattc tctcgaccgt gaatcacttg agaatgaaaa 32400 atatctatag tggcacaaca tagacataaa tgcatgcatc ttctcataat ttttaactcc 32460 tcaggattta gaaacatatc ccagggaata ggaagctctt gcagaacagt aaagctggca 32520 gaacaaggaa gaccacgaac acaacttaca ctatgcatag tcatagtatc acaatctggc 32580 aacagcgggt ggtcttcagt catagaagct cgggtttcat tttcctcaca acgtggtaac 32640 tgggctctgg tgtaagggtg atgtctggcg catgatgtcg agcgtgcgcg caaccttgtc 32700 ataatggagt tgcttcctga cattctcgta ttttgtatag caaaacgcgg ccctggcaga 32760 acacactctt cttcgccttc tatcctgccg cttagcgtgt tccgtgtgat agttcaagta 32820 caaccacact cttaagttgg tcaaaagaat gctggcttca gttgtaatca aaactccatc 32880 gcatctaatc gttctgagga aatcatccaa gcaatgcaac tggattgtgt ttcaagcagg 32940 agaggagagg gaagagacgg aagaaccatg ttaattttta ttccaaacga tctcgcagta 33000 cttcaaattg tagatcgcgc agatggcatc tctcgccccc actgtgttgg tgaaaaagca 33060 cagctagatc aaaagaaatg cgattttcaa ggtgctcaac ggtggcttcc agcaaagcct 33 120 ccacgcgcac atccaagaac aaaagaatac caaaagaagg agcattttct aactcctcaa 33180 tcatcatatt acattcctgc accattccca gataattttc agctttccag ccttgaatta 33240 ttcgtgtcag ttcttgtggt aaatccaatc cacacattac aaacaggtcc cggagggcgc 33300 cctccaccac cattcttaaa cacaccctca taatgacaaa atatcttgct cctgtgtcac 33360 ctgtagcgaa ttgagaatgg caacatcaat tgacatgccc ttggctctaa gttcttcttt 33420 aagttctagt tgtaaaaact ctctcatatt atcaccaaac tgcttagcca gaagcccccc 33480 gggaacaaga gcaggggacg ctacagtgca gtacaagcgc agacctcccc aattggctcc 33540 agcaaaaaca agattggaat aagcatattg ggaaccgcca gtaatatcat cgaagttgct 33600 ggaaatataa tcaggcagag tttcttgtaa aaattgaata aaagaaaaat ttgccaaaaa 33660 aacattcaaa acctctggga tgcaaatgca ataggttacc gcgctgcgct ccaacattgt 33720 tagttttgaa ttagtctgca aaaataaaaa aaaaaacaag cgtcatatca tagtagcctg 33780 acgaacagat ggataaatca gtctttccat cacaagacaa gccacagggt ctccagctcg 33840 accctcgtaa aacctgtcat catgattaaa caacagcacc gaaagttcct cgcggtgacc 33900 agcatgaata attcttgatg aagcatacaa tccagacatg ttagcatcag ttaacgagaa 33960 aaaacagcca acatagcctt tgggtataat tatgcttaat cgtaagtata gcaaagccac 34020 ccctcgcgga tacaaagtaa aaggcacagg agaataaaaa atataattat ttctctgctg 34080 ctgttcaggc aacgtcgccc ccggtccctc taaatacaca tacaaagcct catcagccat 34140 ggcttaccag acaaagtaca gcgggcacac aaagcacaag ctctaaagtg actctccaac 34200 ctctccacaa tatatatata cacaagccct aaactgacgt aatgggagta aagtgtaaaa 34260 aatcccgcca aacccaacac acaccccgaa actgcgtcac cagggaaaag tacagtttca 34320 cttccgcaat cccaacaggc gtaacttcct ctttctcacg gtacgtgata tcccactaac 34380 ttgcaacgtc attttcccac ggtcgcaccg ccccttttag ccgttaaccc cacagccaat 34440 caccacacga tccacacttt ttaaaatcac ctcatttaca tattggcacc attccatcta 34500 taaggtatat tatatagata ga 34522 <210> 97 <211> 966 <212> DNA <213> Artificial Sequence <220> <223> MEMBRANE TETHERED OKT3-SCFV NUCLEIC ACID SEQUENCE <400> 97 atgggatgga gctgtatcat cctcttcttg gtagcaacag ctacaggtgt ccactcccag 60 gtgcagctgc agcagtctgg ggctgaactg gcaagacctg gggcctcagt gaagatgtcc 120 tgcaaggctt ctggctacac ctttactagg tacacgatgc actgggtaaa acagaggcct 180 ggacagggtc tggaatggat tggatacatt aatcctagcc gtggttatac taattacaat 240 cagaagttca aggacaaggc cacattgact acagacaaat cctccagcac agcctacatg 300 caactgagca gcctgacatc tgaggactct gcagtctatt actgtgcaag atattatgat 360 gatcattact gccttgacta ctggggccaa ggcaccactc tcacagtctc ctcaggtggc 420 ggtggctcgg gcggtggtgg atctggtggc ggcggatctg atatcgtgct cactcagtct 480 ccagcaatca tgtctgcatc tccaggggag aaggtcacca tgacctgcag tgccagctca 540 agtgtaagtt acatgaactg gtaccagcag aagtcaggca cctcccccaa aagatggatt 600 tatgacacat ccaaactggc ttctggagtc cctgctcact tcaggggcag tgggtctggg 660 acctcttact ctctcacaat cagcggcatg gaggctgaag atgctgccac ttattactgc 720 cagcagtgga gtagtaaccc attcacgttc ggctcgggga caaagttgga aataaaccgg 780 ggatccgaac aaaaactcat ctcagaagag gatctgaatg ctgtgggcca ggacacgcag 840 gaggtcatcg tggtgccaca ctccttgccc tttaaggtgg tggtgatctc agccatcctg 900 gccctggtgg tgctcaccat catctccctt atcatcctca tcatgctttg gcagaagaag 960 ccacgt 966 <210> 98 <211> 2196 <212> DNA <213> Artificial Sequence <220> <223> Transgene Cassette sequence-NG-348 <400> 98 gcgatcgcca ggcccaccat gggatggagc tgtatcatcc tcttcttggt agcaacagct 60 acaggtgtcc actcccaggt gcagctgcag cagtctgggg ctgaactggc aagacctggg 120 gcctcagtga agatgtcctg caaggcttct ggctacacct ttactaggta cacgatgcac 180 tgggtaaaac agaggcctgg acagggtctg gaatggattg gatacattaa tcctagccgt 240 ggttatacta attacaatca gaagttcaag gacaaggcca cattgactac agacaaatcc 300 tccagcacag cctacatgca actgagcagc ctgacatctg aggactctgc agtctattac 360 tgtgcaagat attatgatga tcattactgc cttgactact ggggccaagg caccactctc 420 acagtctcct caggtggcgg tggctcgggc ggtggtggat ctggtggcgg cggatctgat 480 atcgtgctca ctcagtctcc agcaatcatg tctgcatctc caggggagaa ggtcaccatg 540 acctgcagtg ccagctcaag tgtaagttac atgaactggt accagcagaa gtcaggcacc 600 tcccccaaaa gatggattta tgacacatcc aaactggctt ctggagtccc tgctcacttc 660 aggggcagtg ggtctgggac ctcttactct ctcacaatca gcggcatgga ggctgaagat 720 gctgccactt attactgcca gcagtggagt agtaacccat tcacgttcgg ctcggggaca 780 aagttggaaa taaaccgggg atccgaacaa aaactcatct cagaagagga tctgaatgct 840 gtgggccagg acacgcagga ggtcatcgtg gtgccacact ccttgccctt taaggtggtg 900 gtgatctcag ccatcctggc cctggtggtg ctcaccatca tctcccttat catcctcatc 960 atgctttggc agaagaagcc acgtggaagc ggagctacta acttcagcct gctgaagcag 1020 gctggagacg tggaggagaa ccctggacct ggccacacac ggaggcaggg aacatcacca 1080 tccaagtgtc catacctcaa tttctttcag ctcttggtgc tggctggtct ttctcacttc 1140 tgttcaggtg ttatccacgt gaccaaggaa gtgaaagaag tggcaacgct gtcctgtggt 1200 cacaatgttt ctgttgaaga gctggcacaa actcgcatct actggcaaaa ggagaagaaa 1260 atggtgctga ctatgatgtc tggggacatg aatatatggc ccgagtacaa gaaccggacc 1320 atctttgata tcactaataa cctctccatt gtgatcctgg ctctgcgccc atctgacgag 1380 ggcacatacg agtgtgttgt tctgaagtat gaaaaagacg ctttcaagcg ggaacacctg 1440 gctgaagtga cgttatcagt caaagctgac ttccctacac ctagtatatc tgactttgaa 1500 attccaactt ctaatattag aaggataatt tgctcaacct ctggaggttt tccagagcct 1560 cacctctcct ggttggaaaa tggagaagaa ttaaatgcca tcaacacaac agtttcccaa 1620 gatcctgaaa ctgagctcta tgctgttagc agcaaactgg atttcaatat gacaaccaac 1680 cacagcttca tgtgtctcat caagtatgga catttaagag tgaatcagac cttcaactgg 1740 aatacaacca agcaagagca ttttcctgat aacctgctcc catcctgggc cattacctta 1800 atctcagtaa atggaatttt tgtgatatgc tgcctgacct actgctttgc cccaagatgc 1860 agagagagaa ggaggaatga gagattgaga agggaaagtg tacgccctgt ataagctagc 1920 ttgactgact gagatacagc gtaccttcag ctcacagaca tgataagata cattgatgag 1980 tttggacaaa ccacaactag aatgcagtga aaaaaatgct ttatttgtga aatttgtgat 2040 gctattgctt tatttgtaac cattataagc tgcaataaac aagttaacaa caacaattgc 2100 attcatttta tgtttcaggt tcagggggag gtgtgggagg ttttttaaag caagtaaaac 2160 ctctacaaat gtggtagtcg tcagctatcc tgcagg 2196 <210> 99 <211> 333 <212> PRT <213> Artificial Sequence <220> <223> Membrane anchored form of the anti-human CD3 single chain Fv with C-terminal V5 tag <400> 99 Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly 1 5 10 15 Val His Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg 20 25 30 Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe 35 40 45 Thr Arg Tyr Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu 50 55 60 Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn 65 70 75 80 Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser 85 90 95 Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp 115 120 125 Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 130 135 140 Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser 145 150 155 160 Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys 165 170 175 Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Ser 180 185 190 Gly Thr Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser 195 200 205 Gly Val Pro Ala His Phe Arg Gly Ser Gly Ser Gly Thr Ser Tyr Ser 210 215 220 Leu Thr Ile Ser Gly Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys 225 230 235 240 Gln Gln Trp Ser Ser Asn Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu 245 250 255 Glu Ile Asn Arg Gly Ser Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu 260 265 270 Asn Ala Val Gly Gln Asp Thr Gln Glu Val Ile Val Val Pro His Ser 275 280 285 Leu Pro Phe Lys Val Val Val Ile Ser Ala Ile Leu Ala Leu Val Val 290 295 300 Leu Thr Ile Ile Ser Leu Ile Ile Leu Ile Met Leu Trp Gln Lys Lys 305 310 315 320 Pro Arg Gly Ser Ile Pro Asn Pro Leu Leu Gly Leu Asp 325 330 <210> 100 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> V5 tag (9 amino acid variant) <400> 100 Ile Pro Asn Pro Leu Leu Gly Leu Asp 1 5 <210> 101 <211> 34555 <212> DNA <213> Artificial Sequence <220> <223> NG-348A virus genome sequence comprising a transgene cassette encoding a membrane-anchored chimeric form of the anti-human CD3e scFv with C-terminal V5 tag and CD80 inserted in the region BY <400> 101 tctatctata taatatacct tatagatgga atggtgccaa tatgtaaatg aggtgatttt 60 aaaaagtgtg gatcgtgtgg tgattggctg tggggttaac ggctaaaagg ggcggtgcga 120 ccgtgggaaa atgacgtttt gtgggggtgg agtttttttg caagttgtcg cgggaaatgt 180 gacgcataaa aaggcttttt tctcacggaa ctacttagtt ttcccacggt atttaacagg 240 aaatgaggta gttttgaccg gatgcaagtg aaaattgttg attttcgcgc gaaaactgaa 300 tgaggaagtg tttttctgaa taatgtggta tttatggcag ggtggagtat ttgttcaggg 360 ccaggtagac tttgacccat tacgtggagg tttcgattac cgtgtttttt acctgaattt 420 ccgcgtaccg tgtcaaagtc ttctgttttt acgtaggtgt cagctgatcg ctagggtatt 480 tatacctcag ggtttgtgtc aagaggccac tcttgagtgc cagcgagaag agttttctcc 540 tctgcgccgg cagtttaata ataaaaaaat gagagatttg cgatttctgc ctcaggaaat 600 aatctctgct gagactggaa atgaaatatt ggagcttgtg gtgcacgccc tgatgggaga 660 cgatccggag ccacctgtgc agctttttga gcctcctacg cttcaggaac tgtatgattt 720 agaggtagag ggatcggagg attctaatga ggaagctgta aatggctttt ttaccgattc 780 tatgctttta gctgctaatg aagggttaga attagatccg cctttggaca cttttgatac 840 tccaggggta attgtggaaa gcggtacagg tgtaagaaaa ttacctgatt tgagttccgt 900 ggactgtgat ttgcactgct atgaagacgg gtttcctccg agtgatgagg aggaccatga 960 aaaggagcag tccatgcaga ctgcagcggg tgagggagtg aaggctgcca atgttggttt 1020 tcagttggat tgcccggagc ttcctggaca tggctgtaag tcttgtgaat ttcacaggaa 1080 aaatactgga gtaaaggaac tgttatgttc gctttgttat atgagaacgc actgccactt 1140 tatttacagt aagtgtgttt aagttaaaat ttaaaggaat atgctgtttt tcacatgtat 1200 attgagtgtg agttttgtgc ttcttattat aggtcctgtg tctgatgctg atgaatcacc 1260 atctcctgat tctactacct cacctcctga gattcaagca cctgttcctg tggacgtgcg 1320 caagcccatt cctgtgaagc ttaagcctgg gaaacgtcca gcagtggaaa aacttgagga 1380 cttgttacag ggtggggacg gacctttgga cttgagtaca cggaaacgtc caagacaata 1440 agtgttccat atccgtgttt acttaaggtg acgtcaatat ttgtgtgaca gtgcaatgta 1500 ataaaaatat gttaactgtt cactggtttt tattgctttt tgggcgggga ctcaggtata 1560 taagtagaag cagacctgtg tggttagctc ataggagctg gctttcatcc atggaggttt 1620 gggccatttt ggaagacctt aggaagacta ggcaactgtt agagaacgct tcggacggag 1680 tctccggttt ttggagattc tggttcgcta gtgaattagc tagggtagtt tttaggataa 1740 aacaggacta taaacaagaa tttgaaaagt tgttggtaga ttgcccagga ctttttgaag 1800 ctcttaattt gggccatcag gttcacttta aagaaaaagt tttatcagtt ttagactttt 1860 caaccccagg tagaactgct gctgctgtgg cttttcttac ttttatatta gataaatgga 1920 tcccgcagac tcatttcagc aggggatacg ttttggattt catagccaca gcattgtgga 1980 gaacatggaa ggttcgcaag atgaggacaa tcttaggtta ctggccagtg cagcctttgg 2040 gtgtagcggg aatcctgagg catccaccgg tcatgccagc ggttctggag gaggaacagc 2100 aagaggacaa cccgagagcc ggcctggacc ctccagtgga ggaggcggag tagctgactt 2160 gtctcctgaa ctgcaacggg tgcttactgg atctacgtcc actggacggg ataggggcgt 2220 taagagggag agggcatcta gtggtactga tgctagatct gagttggctt taagtttaat 2280 gagtcgcaga cgtcctgaaa ccatttggtg gcatgaggtt cagaaagagg gaagggatga 2340 agtttctgta ttgcaggaga aatattcact ggaacaggtg aaaacatgtt ggttggagcc 2400 tgaggatgat tgggaggtgg ccattaaaaa ttatgccaag atagctttga ggcctgataa 2460 acagtataag attactagac ggattaatat ccggaatgct tgttacatat ctggaaatgg 2520 ggctgaggtg gtaatagata ctcaagacaa ggcagttatt agatgctgca tgatggatat 2580 gtggcctggg gtagtcggta tggaagcagt aacttttgta aatgttaagt ttaggggaga 2640 tggttataat ggaatagtgt ttatggccaa taccaaactt atattgcatg gttgtagctt 2700 ttttggtttc aacaatacct gtgtagatgc ctggggacag gttagtgtac ggggatgtag 2760 tttctatgcg tgttggattg ccacagctgg cagaaccaag agtcaattgt ctctgaagaa 2820 atgcatattt caaagatgta acctgggcat tctgaatgaa ggcgaagcaa gggtccgcca 2880 ctgcgcttct acagatactg gatgttttat tttgattaag ggaaatgcca gcgtaaagca 2940 taacatgatt tgcggtgctt ccgatgagag gccttatcaa atgctcactt gtgctggtgg 3000 gcattgtaat atgctggcta ctgtgcatat tgtttcccat caacgcaaaa aatggcctgt 3060 ttttgatcac aatgtgatga cgaagtgtac catgcatgca ggtgggcgta gaggaatgtt 3120 tatgccttac cagtgtaaca tgaatcatgt gaaagtgttg ttggaaccag atgccttttc 3180 cagaatgagc ctaacaggaa tttttgacat gaacatgcaa atctggaaga tcctgaggta 3240 tgatgatacg agatcgaggg tacgcgcatg cgaatgcgga ggcaagcatg ccaggttcca 3300 gccggtgtgt gtagatgtga ctgaagatct cagaccggat catttggtta ttgcccgcac 3360 tggagcagag ttcggatcca gtggagaaga aactgactaa ggtgagtatt gggaaaactt 3420 tggggtggga ttttcagatg gacagattga gtaaaaattt gttttttctg tcttgcagct 3480 gtcatgagtg gaaacgcttc ttttaagggg ggagtcttca gcccttatct gacagggcgt 3540 ctcccatcct gggcaggagt tcgtcagaat gttatgggat ctactgtgga tggaagaccc 3600 gtccaacccg ccaattcttc aacgctgacc tatgctactt taagttcttc acctttggac 3660 gcagctgcag ctgccgccgc cgcttctgtt gccgctaaca ctgtgcttgg aatgggttac 3720 tatggaagca tcatggctaa ttccacttcc tctaataacc cttctaccct gactcaggac 3780 aagttacttg tccttttggc ccagctggag gctttgaccc aacgtctggg tgaactttct 3840 cagcaggtgg tcgagttgcg agtacaaact gagtctgctg tcggcacggc aaagtctaaa 3900 taaaaaaatc ccagaatcaa tgaataaata aacaagcttg ttgttgattt aaaatcaagt 3960 gtttttattt catttttcgc gcacggtatg ccctagacca ccgatctcta tcattgagaa 4020 ctcggtggat tttttccagg atcctataga ggtgggattg aatgtttaga tacatgggca 4080 ttaggccgtc tttggggtgg agatagctcc attgaaggga ttcatgctcc ggggtagtgt 4140 tgtaaatcac ccagtcataa caaggtcgca gtgcatggtg ttgcacaata tcttttagaa 4200 gtaggctgat tgccacagat aagcccttgg tgtaggtgtt tacaaaccgg ttgagctggg 4260 atgggtgcat tcggggtgaa attatgtgca ttttggattg gatttttaag ttggcaatat 4320 tgccgccaag atcccgtctt gggttcatgt tatgaaggac caccaagacg gtgtatccgg 4380 tacatttagg aaatttatcg tgcagcttgg atggaaaagc gtggaaaaat ttggagacac 4440 ccttgtgtcc tccaagattt tccatgcact catccatgat aatagcaatg gggccgtggg 4500 cagcggcgcg ggcaaacacg ttccgtgggt ctgacacatc atagttatgt tcctgagtta 4560 aatcatcata agccatttta atgaatttgg ggcggagagt accagattgg ggtatgaatg 4620 ttccttcggg ccccggagca tagttcccct cacagatttg catttcccaa gctttcagtt 4680 ccgagggtgg aatcatgtcc acctgggggg ctatgaaaaa caccgtttct ggggcggggg 4740 tgattaattg tgatgatagc aaatttctga gcaattgaga tttgccacat ccggtggggc 4800 cataaatgat tccgattacg ggttgcaggt ggtagtttag ggaacggcaa ctgccgtctt 4860 ctcgaagcaa gggggccacc tcgttcatca tttcccttac atgcatattt tcccgcacca 4920 aatccattag gaggcgctct cctcctagtg atagaagttc ttgtagtgag gaaaagtttt 4980 tcagcggttt cagaccgtca gccatgggca ttttggagag agtttgctgc aaaagttcta 5040 gtctgttcca cagttcagtg atgtgttcta tggcatctcg atccagcaga cctcctcgtt 5100 tcgcgggttt ggacggctcc tggaataggg tatgagacga tgggcgtcca gcgctgccag 5160 ggttcggtcc ttccagggtc tcagtgttcg agtcagggtt gtttccgtca cagtgaaggg 5220 gtgtgcgcct gcttgggcgc ttgccagggt gcgcttcaga ctcatcctgc tggtcgaaaa 5280 cttctgtcgc ttggcgccct gtatgtcggc caagtagcag tttaccatga gttcgtagtt 5340 gagcgcctcg gctgcgtggc ctttggcgcg gagcttacct ttggaagttt tcttgcatac 5400 cgggcagtat aggcatttca gcgcatacaa cttgggcgca aggaaaacgg attctgggga 5460 gtatgcatct gcgccgcagg aggcgcaaac agtttcacat tccaccagcc aggttaaatc 5520 cggttcattg gggtcaaaaa caagttttcc gccatatttt ttgatgcgtt tcttaccttt 5580 ggtctccatg agttcgtgtc ctcgttgagt gacaaacagg ctgtccgtgt ccccgtagac 5640 tgattttaca ggcctcttct ccagtggagt gcctcggtct tcttcgtaca ggaactctga 5700 ccactctgat acaaaggcgc gcgtccaggc cagcacaaag gaggctatgt gggaggggta 5760 gcgatcgttg tcaaccaggg ggtccacctt ttccaaagta tgcaaacaca tgtcaccctc 5820 ttcaacatcc aggaatgtga ttggcttgta ggtgtatttc acgtgacctg gggtccccgc 5880 tgggggggta taaaaggggg cggttctttg ctcttcctca ctgtcttccg gatcgctgtc 5940 caggaacgtc agctgttggg gtaggtattc cctctcgaag gcgggcatga cctctgcact 6000 caggttgtca gtttctaaga acgaggagga tttgatattg acagtgccgg ttgagatgcc 6060 tttcatgagg ttttcgtcca tctggtcaga aaacacaatt tttttattgt caagtttggt 6120 ggcaaatgat ccatacaggg cgttggataa aagtttggca atggatcgca tggtttggtt 6180 cttttccttg tccgcgcgct ctttggcggc gatgttgagt tggacatact cgcgtgccag 6240 gcacttccat tcggggaaga tagttgttaa ttcatctggc acgattctca cttgccaccc 6300 tcgattatgc aaggtaatta aatccacact ggtggccacc tcgcctcgaa ggggttcatt 6360 ggtccaacag agcctacctc ctttcctaga acagaaaggg ggaagtgggt ctagcataag 6420 ttcatcggga gggtctgcat ccatggtaaa gattcccgga agtaaatcct tatcaaaata 6480 gctgatggga gtggggtcat ctaaggccat ttgccattct cgagctgcca gtgcgcgctc 6540 atatgggtta aggggactgc cccatggcat gggatgggtg agtgcagagg catacatgcc 6600 acagatgtca tagacgtaga tgggatcctc aaagatgcct atgtaggttg gatagcatcg 6660 cccccctctg atacttgctc gcacatagtc atatagttca tgtgatggcg ctagcagccc 6720 cggacccaag ttggtgcgat tgggtttttc tgttctgtag acgatctggc gaaagatggc 6780 gtgagaattg gaagagatgg tgggtctttg aaaaatgttg aaatgggcat gaggtagacc 6840 tacagagtct ctgacaaagt gggcataaga ttcttgaagc ttggttacca gttcggcggt 6900 gacaagtacg tctagggcgc agtagtcaag tgtttcttga atgatgtcat aacctggttg 6960 gtttttcttt tcccacagtt cgcggttgag aaggtattct tcgcgatcct tccagtactc 7020 ttctagcgga aacccgtctt tgtctgcacg gtaagatcct agcatgtaga actgattaac 7080 tgccttgtaa gggcagcagc ccttctctac gggtagagag tatgcttgag cagcttttcg 7140 tagcgaagcg tgagtaaggg caaaggtgtc tctgaccatg actttgagga attggtattt 7200 gaagtcgatg tcgtcacagg ctccctgttc ccagagttgg aagtctaccc gtttcttgta 7260 ggcggggttg ggcaaagcga aagtaacatc attgaagaga atcttgccgg ccctgggcat 7320 gaaattgcga gtgatgcgaa aaggctgtgg tacttccgct cggttattga taacctgggc 7380 agctaggacg atctcgtcga aaccgttgat gttgtgtcct acgatgtata attctatgaa 7440 acgcggcgtg cctctgacgt gaggtagctt actgagctca tcaaaggtta ggtctgtggg 7500 gtcagataag gcgtagtgtt cgagagccca ttcgtgcagg tgaggattcg ctttaaggaa 7560 ggaggaccag aggtccactg ccagtgctgt ttgtaactgg tcccggtact gacgaaaatg 7620 ccgtccgact gccatttttt ctggggtgac gcaatagaag gtttgggggt cctgccgcca 7680 gcgatcccac ttgagtttta tggcgaggtc ataggcgatg ttgacgagcc gctggtctcc 7740 agagagtttc atgaccagca tgaaggggat tagctgcttg ccaaaggacc ccatccaggt 7800 gtaggtttcc acatcgtagg tgagaaagag cctttctgtg cgaggatgag agccaatcgg 7860 gaagaactgg atctcctgcc accagttgga ggaatggctg ttgatgtgat ggaagtagaa 7920 ctccctgcga cgcgccgagc attcatgctt gtgcttgtac agacggccgc agtagtcgca 7980 gcgttgcacg ggttgtatct cgtgaatgag ttgtacctgg cttcccttga cgagaaattt 8040 cagtgggaag ccgaggcctg gcgattgtat ctcgtgcttt actatgttgt ctgcatcggc 8100 ctgttcatct tctgtctcga tggtggtcat gctgacgagc cctcgcggga ggcaagtcca 8160 gacctcggcg cggcaggggc ggagctcgag gacgagagcg cgcaggctgg agctgtccag 8220 ggtcctgaga cgctgcggac tcaggttagt aggcagtgtc aggagattaa cttgcatgat 8280 cttttggagg gcgtgcggga ggttcagata gtacttgatc tcaacgggtc cgttggtgga 8340 gatgtcgatg gcttgcaggg ttccgtgtcc cttgggcgct accaccgtgc ccttgttttt 8400 cattttggac ggcggtggct ctgttgcttc ttgcatgttt agaagcggtg tcgagggcgc 8460 gcaccgggcg gcaggggcgg ctcgggaccc ggcggcatgg ctggcagtgg tacgtcggcg 8520 ccgcgcgcgg gtaggttctg gtactgcgcc ctgagaagac tcgcatgcgc gacgacgcgg 8580 cggttgacat cctggatctg acgcctctgg gtgaaagcta ccggccccgt gagcttgaac 8640 ctgaaagaga gttcaacaga atcaatctcg gtatcgttga cggcggcttg cctaaggatt 8700 tcttgcacgt caccagagtt gtcctggtag gcgatctccg ccatgaactg ctcgatctct 8760 tcctcttgaa gatctccgcg gcccgctctc tcgacggtgg ccgcgaggtc gttggagatg 8820 cgcccaatga gttgagagaa tgcattcatg cccgcctcgt tccagacgcg gctgtagacc 8880 acggccccca cgggatctct cgcgcgcatg accacctggg cgaggttgag ctccacgtgg 8940 cgggtgaaga ccgcatagtt gcataggcgc tggaaaaggt agttgagtgt ggtggcgatg 9000 tgctcggtga cgaagaaata catgatccat cgtctcagcg gcatctcgct gacatcgccc 9060 agagcttcca agcgctccat ggcctcgtag aagtccacgg caaaattaaa aaactgggag 9120 tttcgcgcgg acacggtcaa ctcctcttcc agaagacgga taagttcggc gatggtggtg 9180 cgcacctcgc gctcgaaagc ccctgggatt tcttcctcaa tctcttcttc ttccactaac 9240 atctcttcct cttcaggtgg ggctgcagga ggagggggaa cgcggcgacg ccggcggcgc 9300 acgggcagac ggtcgatgaa tctttcaatg acctctccgc ggcggcggcg catggtttca 9360 gtgacggcgc ggccgttctc gcgcggtcgc agagtaaaaa caccgccgcg catctcctta 9420 aagtggtgac tgggaggttc tccgtttggg agggagaggg cgctgattat acattttatt 9480 aattggcccg tagggactgc acgcagagat ctgatcgtgt caagatccac gggatctgaa 9540 aacctttcga cgaaagcgtc taaccagtca cagtcacaag gtaggctgag tacggcttct 9600 tgtgggcggg ggtggttatg tgttcggtct gggtcttctg tttcttcttc atctcgggaa 9660 ggtgagacga tgctgctggt gatgaaatta aagtaggcag ttctaagacg gcggatggtg 9720 gcgaggagca ccaggtcttt gggtccggct tgctggatac gcaggcgatt ggccattccc 9780 caagcattat cctgacatct agcaagatct ttgtagtagt cttgcatgag ccgttctacg 9840 ggcacttctt cctcacccgt tctgccatgc atacgtgtga gtccaaatcc gcgcattggt 9900 tgtaccagtg ccaagtcagc tacgactctt tcggcgagga tggcttgctg tacttgggta 9960 agggtggctt gaaagtcatc aaaatccaca aagcggtggt aagctcctgt attaatggtg 10020 taagcacagt tggccatgac tgaccagtta actgtctggt gaccagggcg cacgagctcg 10080 gtgtatttaa ggcgcgaata ggcgcgggtg tcaaagatgt aatcgttgca ggtgcgcacc 10140 agatactggt accctataag aaaatgcggc ggtggttggc ggtagagagg ccatcgttct 10200 gtagctggag cgccaggggc gaggtcttcc aacataaggc ggtgatagcc gtagatgtac 10260 ctggacatcc aggtgattcc tgcggcggta gtagaagccc gaggaaactc gcgtacgcgg 10320 ttccaaatgt tgcgtagcgg catgaagtag ttcattgtag gcacggtttg accagtgagg 10380 cgcgcgcagt cattgatgct ctatagacac ggagaaaatg aaagcgttca gcgactcgac 10440 tccgtagcct ggaggaacgt gaacgggttg ggtcgcggtg taccccggtt cgagacttgt 10500 actcgagccg gccggagccg cggctaacgt ggtattggca ctcccgtctc gacccagcct 10560 acaaaaatcc aggatacgga atcgagtcgt tttgctggtt tccgaatggc agggaagtga 10620 gtcctatttt ttttttttgc cgctcagatg catcccgtgc tgcgacagat gcgcccccaa 10680 caacagcccc cctcgcagca gcagcagcag caatcacaaa aggctgtccc tgcaactact 10740 gcaactgccg ccgtgagcgg tgcgggacag cccgcctatg atctggactt ggaagagggc 10800 gaaggactgg cacgtctagg tgcgccttca cccgagcggc atccgcgagt tcaactgaaa 10860 aaagattctc gcgaggcgta tgtgccccaa cagaacctat ttagagacag aagcggcgag 10920 gagccggagg agatgcgagc ttcccgcttt aacgcgggtc gtgagctgcg tcacggtttg 10980 gaccgaagac gagtgttgcg ggacgaggat ttcgaagttg atgaaatgac agggatcagt 11040 cctgccaggg cacacgtggc tgcagccaac cttgtatcgg cttacgagca gacagtaaag 11 100 gaagagcgta acttccaaaa gtcttttaat aatcatgtgc gaaccctgat tgcccgcgaa 11160 gaagttaccc ttggtttgat gcatttgtgg gatttgatgg aagctatcat tcagaaccct 11220 actagcaaac ctctgaccgc ccagctgttt ctggtggtgc aacacagcag agacaatgag 11280 gctttcagag aggcgctgct gaacatcacc gaacccgagg ggagatggtt gtatgatctt 11340 atcaacattc tacagagtat catagtgcag gagcggagcc tgggcctggc cgagaaggtg 11400 gctgccatca attactcggt tttgagcttg ggaaaatatt acgctcgcaa aatctacaag 11460 actccatacg ttcccataga caaggaggtg aagatagatg ggttctacat gcgcatgacg 11520 ctcaaggtct tgaccctgag cgatgatctt ggggtgtatc gcaatgacag aatgcatcgc 11580 gcggttagcg ccagcaggag gcgcgagtta agcgacaggg aactgatgca cagtttgcaa 11640 agagctctga ctggagctgg aaccgagggt gagaattact tcgacatggg agctgacttg 11700 cagtggcagc ctagtcgcag ggctctgagc gccgcgacgg caggatgtga gcttccttac 11760 atagaagagg cggatgaagg cgaggaggaa gagggcgagt acttggaaga ctgatggcac 11820 aacccgtgtt ttttgctaga tggaacagca agcaccggat cccgcaatgc gggcggcgct 11880 gcagagccag ccgtccggca ttaactcctc ggacgattgg acccaggcca tgcaacgtat 11940 catggcgttg acgactcgca accccgaagc ctttagacag caaccccagg ccaaccgtct 12000 atcggccatc atggaagctg tagtgccttc ccgctctaat cccactcatg agaaggtcct 12060 ggccatcgtg aacgcgttgg tggagaacaa agctattcgt ccagatgagg ccggactggt 12120 atacaacgct ctcttagaac gcgtggctcg ctacaacagt agcaatgtgc aaaccaattt 12180 ggaccgtatg ataacagatg tacgcgaagc cgtgtctcag cgcgaaaggt tccagcgtga 12240 tgccaacctg ggttcgctgg tggcgttaaa tgctttcttg agtactcagc ctgctaatgt 12300 gccgcgtggt caacaggatt atactaactt tttaagtgct ttgagactga tggtatcaga 12360 agtacctcag agcgaagtgt atcagtccgg tcctgattac ttctttcaga ctagcagaca 12420 gggcttgcag acggtaaatc tgagccaagc ttttaaaaac cttaaaggtt tgtggggagt 12480 gcatgccccg gtaggagaaa gagcaaccgt gtctagcttg ttaactccga actcccgcct 12540 attattactg ttggtagctc ctttcaccga cagcggtagc atcgaccgta attcctattt 12600 gggttaccta ctaaacctgt atcgcgaagc catagggcaa agtcaggtgg acgagcagac 12660 ctatcaagaa attacccaag tcagtcgcgc tttgggacag gaagacactg gcagtttgga 12720 agccactctg aacttcttgc ttaccaatcg gtctcaaaag atccctcctc aatatgctct 12780 tactgcggag gaggagagga tccttagata tgtgcagcag agcgtgggat tgtttctgat 12840 gcaagagggg gcaactccga ctgcagcact ggacatgaca gcgcgaaata tggagcccag 12900 catgtatgcc agtaaccgac ctttcattaa caaactgctg gactacttgc acagagctgc 12960 cgctatgaac tctgattatt tcaccaatgc catcttaaac ccgcactggc tgcccccacc 13020 tggtttctac acgggcgaat atgacatgcc cgaccctaat gacggatttc tgtgggacga 13080 cgtggacagc gatgtttttt cacctctttc tgatcatcgc acgtggaaaa aggaaggcgg 13140 cgatagaatg cattcttctg catcgctgtc cggggtcatg ggtgctaccg cggctgagcc 13200 cgagtctgca agtccttttc ctagtctacc cttttctcta cacagtgtac gtagcagcga 13260 agtgggtaga ataagtcgcc cgagtttaat gggcgaagag gagtatctaa acgattcctt 13320 gctcagaccg gcaagagaaa aaaatttccc aaacaatgga atagaaagtt tggtggataa 13380 aatgagtaga tggaagactt atgctcagga tcacagagac gagcctggga tcatggggat 13440 tacaagtaga gcgagccgta gacgccagcg ccatgacaga cagaggggtc ttgtgtggga 13500 cgatgaggat tcggccgatg atagcagcgt gctggacttg ggtgggagag gaaggggcaa 13560 cccgtttgct catttgcgcc ctcgcttggg tggtatgttg taaaaaaaaa taaaaaaaaa 13620 actcaccaag gccatggcga cgagcgtacg ttcgttcttc tttattatct gtgtctagta 13680 taatgaggcg agtcgtgcta ggcggagcgg tggtgtatcc ggagggtcct cctccttcgt 13740 acgagagcgt gatgcagcag cagcaggcga cggcggtgat gcaatcccca ctggaggctc 13800 cctttgtgcc tccgcgatac ctggcaccta cggagggcag aaacagcatt cgttattcgg 13860 aactggcacc tcagtacgat accaccaggt tgtatctggt ggacaacaag tcggcggaca 13920 ttgcttctct gaactatcag aatgaccaca gcaacttctt gaccacggtg gtgcaaaaca 13980 atgactttac ccctacggaa gccagcaccc agaccattaa ctttgatgaa cgatcgcggt 14040 ggggcggtca gctaaagacc atcatgcata ctaacatgcc aaacgtgaac gagtatatgt 14100 ttagtaacaa gttcaaagcg cgtgtgatgg tgtccagaaa acctcccgac ggtgctgcag 14160 ttggggatac ttatgatcac aagcaggata ttttgaaata tgagtggttc gagtttactt 14220 tgccagaagg caacttttca gttactatga ctattgattt gatgaacaat gccatcatag 14280 ataattactt gaaagtgggt agacagaatg gagtgcttga aagtgacatt ggtgttaagt 14340 tcgacaccag gaacttcaag ctgggatggg atcccgaaac caagttgatc atgcctggag 14400 tgtatacgta tgaagccttc catcctgaca ttgtcttact gcctggctgc ggagtggatt 14460 ttaccgagag tcgtttgagc aaccttcttg gtatcagaaa aaaacagcca tttcaagagg 14520 gttttaagat tttgtatgaa gatttagaag gtggtaatat tccggccctc ttggatgtag 14580 atgcctatga gaacagtaag aaagaacaaa aagccaaaat agaagctgct acagctgctg 14640 cagaagctaa ggcaaacata gttgccagcg actctacaag ggttgctaac gctggagagg 14700 tcagaggaga caattttgcg ccaacacctg ttccgactgc agaatcatta ttggccgatg 14760 tgtctgaagg aacggacgtg aaactcacta ttcaacctgt agaaaaagat agtaagaata 14820 gaagctataa tgtgttggaa gacaaaatca acacagccta tcgcagttgg tatctttcgt 14880 acaattatgg cgatcccgaa aaaggagtgc gttcctggac attgctcacc acctcagatg 14940 tcacctgcgg agcagagcag gtctactggt cgcttccaga catgatgaag gatcctgtca 15000 ctttccgctc cactagacaa gtcagtaact accctgtggt gggtgcagag cttatgcccg 15060 tcttctcaaa gagcttctac aacgaacaag ctgtgtactc ccagcagctc cgccagtcca 15120 cctcgcttac gcacgtcttc aaccgctttc ctgagaacca gattttaatc cgtccgccgg 15180 cgcccaccat taccaccgtc agtgaaaacg ttcctgctct cacagatcac gggaccctgc 15240 cgttgcgcag cagtatccgg ggagtccaac gtgtgaccgt tactgacgcc agacgccgca 15300 cctgtcccta cgtgtacaag gcactgggca tagtcgcacc gcgcgtcctt tcaagccgca 15360 ctttctaaaa aaaaaaaaaa tgtccattct tatctcgccc agtaataaca ccggttgggg 15420 tctgcgcgct ccaagcaaga tgtacggagg cgcacgcaaa cgttctaccc aacatcctgt 15480 ccgtgttcgc ggacattttc gcgctccatg gggcgccctc aagggccgca ctcgcgttcg 15540 aaccaccgtc gatgatgtaa tcgatcaggt ggttgccgac gcccgtaatt atactcctac 15600 tgcgcctaca tctactgtgg atgcagttat tgacagtgta gtggctgacg ctcgcaacta 15660 tgctcgacgt aagagccggc gaaggcgcat tgccagacgc caccgagcta ccactgccat 15720 gcgagccgca agagctctgc tacgaagagc tagacgcgtg gggcgaagag ccatgcttag 15780 ggcggccaga cgtgcagctt cgggcgccag cgccggcagg tcccgcaggc aagcagccgc 15840 tgtcgcagcg gcgactattg ccgacatggc ccaatcgcga agaggcaatg tatactgggt 15900 gcgtgacgct gccaccggtc aacgtgtacc cgtgcgcacc cgtccccctc gcacttagaa 15960 gatactgagc agtctccgat gttgtgtccc agcggcgagg atgtccaagc gcaaatacaa 16020 ggaagaaatg ctgcaggtta tcgcacctga agtctacggc caaccgttga aggatgaaaa 16080 aaaaccccgc aaaatcaagc gggttaaaaa ggacaaaaaa gaagaggaag atggcgatga 16140 tgggctggcg gagtttgtgc gcgagtttgc cccacggcga cgcgtgcaat ggcgtgggcg 16200 caaagttcga catgtgttga gacctggaac ttcggtggtc tttacacccg gcgagcgttc 16260 aagcgctact tttaagcgtt cctatgatga ggtgtacggg gatgatgata ttcttgagca 16320 ggcggctgac cgattaggcg agtttgctta tggcaagcgt agtagaataa cttccaagga 16380 tgagacagtg tcgataccct tggatcatgg aaatcccacc cctagtctta aaccggtcac 16440 tttgcagcaa gtgttacccg taactccgcg aacaggtgtt aaacgcgaag gtgaagattt 16500 gtatcccact atgcaactga tggtacccaa acgccagaag ttggaggacg ttttggagaa 16560 agtaaaagtg gatccagata ttcaacctga ggttaaagtg agacccatta agcaggtagc 16620 gcctggtctg ggggtacaaa ctgtagacat taagattccc actgaaagta tggaagtgca 16680 aactgaaccc gcaaagccta ctgccacctc cactgaagtg caaacggatc catggatgcc 16740 catgcctatt acaactgacg ccgccggtcc cactcgaaga tcccgacgaa agtacggtcc 16800 agcaagtctg ttgatgccca attatgttgt acacccatct attattccta ctcctggtta 16860 ccgaggcact cgctactatc gcagccgaaa cagtacctcc cgccgtcgcc gcaagacacc 16920 tgcaaatcgc agtcgtcgcc gtagacgcac aagcaaaccg actcccggcg ccctggtgcg 16980 gcaagtgtac cgcaatggta gtgcggaacc tttgacactg ccgcgtgcgc gttaccatcc 17040 gagtatcatc acttaatcaa tgttgccgct gcctccttgc agatatggcc ctcacttgtc 17100 gccttcgcgt tcccatcact ggttaccgag gaagaaactc gcgccgtaga agagggatgt 17160 tgggacgcgg aatgcgacgc tacaggcgac ggcgtgctat ccgcaagcaa ttgcggggtg 17220 gttttttacc agccttaatt ccaattatcg ctgctgcaat tggcgcgata ccaggcatag 17280 cttccgtggc ggttcaggcc tcgcaacgac attgacattg gaaaaaaacg tataaataaa 17340 aaaaaaaaaa tacaatggac tctgacactc ctggtcctgt gactatgttt tcttagagat 17400 ggaagacatc aatttttcat ccttggctcc gcgacacggc acgaagccgt acatgggcac 17460 ctggagcgac atcggcacga gccaactgaa cgggggcgcc ttcaattgga gcagtatctg 17520 gagcgggctt aaaaattttg gctcaaccat aaaaacatac gggaacaaag cttggaacag 17580 cagtacagga caggcgctta gaaataaact taaagaccag aacttccaac aaaaagtagt 17640 cgatgggata gcttccggca tcaatggagt ggtagatttg gctaaccagg ctgtgcagaa 17700 aaagataaac agtcgtttgg acccgccgcc agcaacccca ggtgaaatgc aagtggagga 17760 agaaattcct ccgccagaaa aacgaggcga caagcgtccg cgtcccgatt tggaagagac 17820 gctggtgacg cgcgtagatg aaccgccttc ttatgaggaa gcaacgaagc ttggaatgcc 17880 caccactaga ccgatagccc caatggccac cggggtgatg aaaccttctc agttgcatcg 17940 acccgtcacc ttggatttgc cccctccccc tgctgctact gctgtacccg cttctaagcc 18000 tgtcgctgcc ccgaaaccag tcgccgtagc caggtcacgt cccgggggcg ctcctcgtcc 18060 aaatgcgcac tggcaaaata ctctgaacag catcgtgggt ctaggcgtgc aaagtgtaaa 18 120 acgccgtcgc tgcttttaat taaatatgga gtagcgctta acttgcctat ctgtgtatat 18180 gtgtcattac acgccgtcac agcagcagag gaaaaaagga agaggtcgtg cgtcgacgct 18240 gagttacttt caagatggcc accccatcga tgctgcccca atgggcatac atgcacatcg 18300 ccggacagga tgcttcggag tacctgagtc cgggtctggt gcagttcgcc cgcgccacag 18360 acacctactt caatctggga aataagttta gaaatcccac cgtagcgccg acccacgatg 18420 tgaccaccga ccgtagccag cggctcatgt tgcgcttcgt gcccgttgac cgggaggaca 18480 atacatactc ttacaaagtg cggtacaccc tggccgtggg cgacaacaga gtgctggata 18540 tggccagcac gttctttgac attaggggtg tgttggacag aggtcccagt ttcaaaccct 18600 attctggtac ggcttacaac tccctggctc ctaaaggcgc tccaaataca tctcagtgga 18660 ttgcagaagg tgtaaaaaat acaactggtg aggaacacgt aacagaagag gaaaccaata 18720 ctactactta cacttttggc aatgctcctg taaaagctga agctgaaatt acaaaagaag 18780 gactcccagt aggtttggaa gtttcagatg aagaaagtaa accgatttat gctgataaaa 18840 catatcagcc agaacctcag ctgggagatg aaacttggac tgaccttgat ggaaaaaccg 18900 aaaagtatgg aggcagggct ctcaaacccg atactaagat gaaaccatgc tacgggtcct 18960 ttgccaaacc tactaatgtg aaaggcggtc aggcaaaaca aaaaacaacg gagcagccaa 19020 atcagaaagt cgaatatgat atcgacatgg agttttttga tgcggcatcg cagaaaacaa 19080 acttaagtcc taaaattgtc atgtatgcag aaaatgtaaa tttggaaact ccagacactc 19140 atgtagtgta caaacctgga acagaagaca caagttccga agctaatttg ggacaacaat 19200 ctatgcccaa cagacccaac tacattggct tcagagataa ctttattgga cttatgtact 19260 ataacagtac tggtaacatg ggggtgctgg ctggtcaagc gtctcagtta aatgcagtgg 19320 ttgacttgca ggacagaaac acagaacttt cttaccaact cttgcttgac tctctgggcg 19380 acagaaccag atactttagc atgtggaatc aggctgtgga cagttatgat cctgatgtac 19440 gtgttattga aaatcatggt gtggaagatg aacttcccaa ctactgtttt ccactggacg 19500 gcataggtgt tccaacaacc agttacaaat caatagttcc aaatggagac aatgcgccta 19560 attggaagga acctgaagta aatggaacaa gtgagatcgg acagggtaat ttgtttgcca 19620 tggaaattaa ccttcaagcc aatctatggc gaagtttcct ttattccaat gtggctctat 19680 atctcccaga ctcgtacaaa tacaccccgt ccaatgtcac tcttccagaa aacaaaaaca 19740 cctacgacta catgaacggg cgggtggtgc cgccatctct agtagacacc tatgtgaaca 19800 ttggtgccag gtggtctctg gatgccatgg acaatgtcaa cccattcaac caccaccgta 19860 acgctggctt gcgttaccga tccatgcttc tgggtaacgg acgttatgtg cctttccaca 19920 tacaagtgcc tcaaaaattc ttcgctgtta aaaacctgct gcttctccca ggctcctaca 19980 cttatgagtg gaactttagg aaggatgtga acatggttct acagagttcc ctcggtaacg 20040 acctgcgggt agatggcgcc agcatcagtt tcacgagcat caacctctat gctacttttt 20100 tccccatggc tcacaacacc gcttccaccc ttgaagccat gctgcggaat gacaccaatg 20160 atcagtcatt caacgactac ctatctgcag ctaacatgct ctaccccatt cctgccaatg 20220 caaccaatat tcccatttcc attccttctc gcaactgggc ggctttcaga ggctggtcat 20280 ttaccagact gaaaaccaaa gaaactccct ctttggggtc tggatttgac ccctactttg 20340 tctattctgg ttctattccc tacctggatg gtaccttcta cctgaaccac acttttaaga 20400 aggtttccat catgtttgac tcttcagtga gctggcctgg aaatgacagg ttactatctc 20460 ctaacgaatt tgaaataaag cgcactgtgg atggcgaagg ctacaacgta gcccaatgca 20520 acatgaccaa agactggttc ttggtacaga tgctcgccaa ctacaacatc ggctatcagg 20580 gcttctacat tccagaagga tacaaagatc gcatgtattc atttttcaga aacttccagc 20640 ccatgagcag gcaggtggtt gatgaggtca attacaaaga cttcaaggcc gtcgccatac 20700 cctaccaaca caacaactct ggctttgtgg gttacatggc tccgaccatg cgccaaggtc 20760 aaccctatcc cgctaactat ccctatccac tcattggaac aactgccgta aatagtgtta 20820 cgcagaaaaa gttcttgtgt gacagaacca tgtggcgcat accgttctcg agcaacttca 20880 tgtctatggg ggcccttaca gacttgggac agaatatgct ctatgccaac tcagctcatg 20940 ctctggacat gacctttgag gtggatccca tggatgagcc caccctgctt tatcttctct 21000 tcgaagtttt cgacgtggtc agagtgcatc agccacaccg cggcatcatc gaggcagtct 21060 acctgcgtac accgttctcg gccggtaacg ctaccacgta agaagcttct tgcttcttgc 21120 aaatagcagc tgcaaccatg gcctgcggat cccaaaacgg ctccagcgag caagagctca 21180 gagccattgt ccaagacctg ggttgcggac cctatttttt gggaacctac gataagcgct 21240 tcccggggtt catggccccc gataagctcg cctgtgccat tgtaaatacg gccggacgtg 21300 agacgggggg agagcactgg ttggctttcg gttggaaccc acgttctaac acctgctacc 21360 tttttgatcc ttttggattc tcggatgatc gtctcaaaca gatttaccag tttgaatatg 21420 agggtctcct gcgccgcagc gctcttgcta ccaaggaccg ctgtattacg ctggaaaaat 21480 ctacccagac cgtgcagggt ccccgttctg ccgcctgcgg acttttctgc tgcatgttcc 21540 ttcacgcctt tgtgcactgg cctgaccgtc ccatggacgg aaaccccacc atgaaattgc 21600 taactggagt gccaaacaac atgcttcatt ctcctaaagt ccagcccacc ctgtgtgaca 21660 atcaaaaagc actctaccat tttcttaata cccattcgcc ttattttcgc tcccatcgta 21720 cacacatcga aagggccact gcgttcgacc gtatggatgt tcaataatga ctcatgtaaa 21780 caacgtgttc aataaacatc actttatttt tttacatgta tcaaggctct gcattactta 21840 tttatttaca agtcgaatgg gttctgacga gaatcagaat gacccgcagg cagtgatacg 21900 ttgcggaact gatacttggg ttgccacttg aattcgggaa tcaccaactt gggaaccggt 21960 atatcgggca ggatgtcact ccacagcttt ctggtcagct gcaaagctcc aagcaggtca 22020 ggagccgaaa tcttgaaatc acaattagga ccagtgcttt gagcgcgaga gttgcggtac 22080 accggattgc agcactgaaa caccatcagc gacggatgtc tcacgcttgc cagcacggtg 22140 ggatctgcaa tcatgcccac atccagatct tcagcattgg caatgctgaa cggggtcatc 22200 ttgcaggtct gcctacccat ggcgggcacc caattaggct tgtggttgca atcgcagtgc 22260 agggggatca gtatcatctt ggcctgatcc tgtctgattc ctggatacac ggctctcatg 22320 aaagcatcat attgcttgaa agcctgctgg gctttactac cctcggtata aaacatcccg 22380 caggacctgc tcgaaaactg gttagctgca cagccggcat cattcacaca gcagcgggcg 22440 tcattgttag ctatttgcac cacacttctg ccccagcggt tttgggtgat tttggttcgc 22500 tcgggattct cctttaaggc tcgttgtccg ttctcgctgg ccacatccat ctcgataatc 22560 tgctccttct gaatcataat attgccatgc aggcacttca gcttgccctc ataatcattg 22620 cagccatgag gccacaacgc acagcctgta cattcccaat tatggtgggc gatctgagaa 22680 aaagaatgta tcattccctg cagaaatctt cccatcatcg tgctcagtgt cttgtgacta 22740 gtgaaagtta actggatgcc tcggtgctcc tcgtttacgt actggtgaca gatgcgcttg 22800 tattgttcgt gttgctcagg cattagttta aaagaggttc taagttcgtt atccagcctg 22860 tacttctcca tcagcagaca catcacttcc atgcctttct cccaagcaga caccaggggc 22920 aagctaatcg gattcttaac agtgcaggca gcagctcctt tagccagagg gtcatcttta 22980 gcgatcttct caatgcttct tttgccatcc ttctcaacga tgcgcacggg cgggtagctg 23040 aaacccactg ctacaagttg cgcctcttct ctttcttctt cgctgtcttg actgatgtct 23100 tgcatgggga tatgtttggt cttccttggc ttctttttgg ggggtatcgg aggaggagga 23160 ctgtcgctcc gttccggaga cagggaggat tgtgacgttt cgctcaccat taccaactga 23220 ctgtcggtag aagaacctga ccccacacgg cgacaggtgt ttctcttcgg gggcagaggt 23280 ggaggcgatt gcgaagggct gcggtccgac ctggaaggcg gatgactggc agaacccctt 23340 ccgcgttcgg gggtgtgctc cctgtggcgg tcgcttaact gatttccttc gcggctggcc 23400 attgtgttct cctaggcaga gaaacaacag acatggaaac tcagccattg ctgtcaacat 23460 cgccacgagt gccatcacat ctcgtcctca gcgacgagga aaaggagcag agcttaagca 23520 ttccaccgcc cagtcctgcc accacctcta ccctagaaga taaggaggtc gacgcatctc 23580 atgacatgca gaataaaaaa gcgaaagagt ctgagacaga catcgagcaa gacccgggct 23640 atgtgacacc ggtggaacac gaggaagagt tgaaacgctt tctagagaga gaggatgaaa 23700 actgcccaaa acaacgagca gataactatc accaagatgc tggaaatagg gatcagaaca 23760 ccgactacct catagggctt gacggggaag acgcgctcct taaacatcta gcaagacagt 23820 cgctcatagt caaggatgca ttattggaca gaactgaagt gcccatcagt gtggaagagc 23880 tcagccgcgc ctacgagctt aacctctttt cacctcgtac tccccccaaa cgtcagccaa 23940 acggcacctg cgagccaaat cctcgcttaa acttttatcc agcttttgct gtgccagaag 24000 tactggctac ctatcacatc ttttttaaaa atcaaaaaat tccagtctcc tgccgcgcta 24060 atcgcacccg cgccgatgcc ctactcaatc tgggacctgg ttcacgctta cctgatatag 24120 cttccttgga agaggttcca aagatcttcg agggtctggg caataatgag actcgggccg 24180 caaatgctct gcaaaaggga gaaaatggca tggatgagca tcacagcgtt ctggtggaat 24 240 tggaaggcga taatgccaga ctcgcagtac tcaagcgaag catcgaggtc acacacttcg 24300 catatcccgc tgtcaacctg ccccctaaag tcatgacggc ggtcatggac cagttactca 24360 ttaagcgcgc aagtcccctt tcagaagaca tgcatgaccc agatgcctgt gatgagggta 24420 aaccagtggt cagtgatgag cagctaaccc gatggctggg caccgactct cccagggatt 24480 tggaagagcg tcgcaagctt atgatggccg tggtgctggt taccgtagaa ctagagtgtc 24540 tccgacgttt ctttaccgat tcagaaacct tgcgcaaact cgaagagaat ctgcactaca 24600 cttttagaca cggctttgtg cggcaggcat gcaagatatc taacgtggaa ctcaccaacc 24660 tggtttccta catgggtatt ctgcatgaga atcgcctagg acaaagcgtg ctgcacagca 24720 ccctgaaggg ggaagcccgc cgtgattaca tccgcgattg tgtctatctg tacctgtgcc 24780 acacgtggca aaccggcatg ggtgtatggc agcaatgttt agaagaacag aacttgaaag 24840 agcttgacaa gctcttacag aaatctctta aggttctgtg gacagggttc gacgagcgca 24900 ccgtcgcttc cgacctggca gacctcatct tcccagagcg tctcagggtt actttgcgaa 24960 acggattgcc tgactttatg agccagagca tgcttaacaa ttttcgctct ttcatcctgg 25020 aacgctccgg tatcctgccc gccacctgct gcgcactgcc ctccgacttt gtgcctctca 25080 cctaccgcga gtgccccccg ccgctatgga gtcactgcta cctgttccgt ctggccaact 25 140 atctctccta ccactcggat gtgatcgagg atgtgagcgg agacggcttg ctggagtgtc 25200 actgccgctg caatctgtgc acgccccacc ggtccctagc ttgcaacccc cagttgatga 25260 gcgaaaccca gataataggc acctttgaat tgcaaggccc cagcagccaa ggcgatgggt 25320 cttctcctgg gcaaagttta aaactgaccc cgggactgtg gacctccgcc tacttgcgca 25380 agtttgctcc ggaagattac cacccctatg aaatcaagtt ctatgaggac caatcacagc 25440 ctccaaaggc cgaactttcg gcctgcgtca tcacccaggg ggcaattctg gcccaattgc 25500 aagccatcca aaaatcccgc caagaatttc tactgaaaaa gggtaagggg gtctaccttg 25560 acccccagac cggcgaggaa ctcaacacaa ggttccctca ggatgtccca acgacgagaa 25620 aacaagaagt tgaaggtgca gccgccgccc ccagaagata tggaggaaga ttgggacagt 25680 caggcagagg aggcggagga ggacagtctg gaggacagtc tggaggaaga cagtttggag 25740 gaggaaaacg aggaggcaga ggaggtggaa gaagtaaccg ccgacaaaca gttatcctcg 25800 gctgcggaga caagcaacag cgctaccatc tccgctccga gtcgaggaac ccggcggcgt 25860 cccagcagta gatgggacga gaccggacgc ttcccgaacc caaccagcgc ttccaagacc 25920 ggtaagaagg atcggcaggg atacaagtcc tggcgggggc ataagaatgc catcatctcc 25980 tgcttgcatg agtgcggggg caacatatcc ttcacgcggc gctacttgct attccaccat 26040 ggggtgaact ttccgcgcaa tgttttgcat tactaccgtc acctccacag cccctactat 26100 agccagcaaa tcccggcagt ctcgacagat aaagacagcg gcggcgacct ccaacagaaa 26160 accagcagcg gcagttagaa aatacacaac aagtgcagca acaggaggat taaagattac 26220 agccaacgag ccagcgcaaa cccgagagtt aagaaatcgg atctttccaa ccctgtatgc 26280 catcttccag cagagtcggg gtcaagagca ggaactgaaa ataaaaaacc gatctctgcg 26340 ttcgctcacc agaagttgtt tgtatcacaa gagcgaagat caacttcagc gcactctcga 26400 ggacgccgag gctctcttca acaagtactg cgcgctgact cttaaagagt aggcagcgac 26460 cgcgcttatt caaaaaaggc gggaattaca tcatcctcga catgagtaaa gaaattccca 26520 cgccttacat gtggagttat caaccccaaa tgggattggc ggcaggcgcc tcccaggact 26580 actccacccg catgaattgg ctcagcgccg ggccttctat gatttctcga gttaatgata 26640 tacgcgccta ccgaaaccaa atacttttgg aacagtcagc tcttaccacc acgccccgcc 26700 aacaccttaa tcccagaaat tggcccgccg ccctagtgta ccaggaaagt cccgctccca 26760 ccactgtatt acttcctcga gacgcccagg ccgaagtcca aatgactaat gcaggtgcgc 26820 agttagctgg cggctccacc ctatgtcgtc acaggcctcg gcataatata aaacgcctga 26880 tgatcagagg ccgaggtatc cagctcaacg acgagtcggt gagctctccg cttggtctac 26940 gaccagacgg aatctttcag attgccggct gcgggagatc ttccttcacc cctcgtcagg 27000 ctgttctgac tttggaaagt tcgtcttcgc aaccccgctc gggcggaatc gggaccgttc 27060 aatttgtgga ggagtttact ccctctgtct acttcaaccc cttctccgga tctcctgggc 27120 attacccgga cgagttcata ccgaacttcg acgcgattag cgagtcagtg gacggctacg 27180 attgatgtct ggtgacgcgg ctgagctatc tcggctgcga catctagacc actgccgccg 27240 ctttcgctgc tttgcccggg aactcattga gttcatctac ttcgaactcc ccaaggatca 27300 ccctcaaggt ccggcccacg gagtgcggat ttctatcgaa ggcaaaatag actctcgcct 27360 gcaacgaatt ttctcccagc ggcccgtgct gatcgagcga gaccagggaa acaccacggt 27420 ttccatctac tgcatttgta atcaccccgg attgcatgaa agcctttgct gtcttatgtg 27480 tactgagttt aataaaaact gaattaagac tctcctacgg actgccgctt cttcaacccg 27540 gattttacaa ccagaagaac gaaacttttc ctgtcgtcca ggactctgtt aacttcacct 27600 ttcctactca caaactagaa gctcaacgac tacaccgctt ttccagaagc attttcccta 27660 ctaatactac tttcaaaacc ggaggtgagc tccaaggtct tcctacagaa aacccttggg 27720 tggaagcggg ccttgtagtg ctaggaattc ttgcgggtgg gcttgtgatt attctttgct 27780 acctatacac accttgcttc actttcttag tggtgttgtg gtattggttt aaaaaatggg 27840 gcccatacta gtcttgcttg ttttactttc gcttttggaa ccgggttctg ccaattacga 27900 tccatgtcta gacttcgacc cagaaaactg cacacttact tttgcacccg acacaagccg 27960 catctgtgga gttcatcgcc tctcttacga acttggcccc caacgacaaa aatttacctg 28020 catggtggga atcaacccca tagttatcac ccagcaaagt ggagatacta agggttgcat 28080 tcactgctcc tgcgattcca tcgagtgcac ctacaccctg ctgaagaccc tatgcggcct 28140 aagagacctg ctaccaatga attaaaaaat gattaataaa aaatcactta cttgaaatca 28200 gcaataaggt ctctgttgaa attttctccc agcagcacct cacttccctc ttcccaactc 28260 tggtattcta aaccccgttc agcggcatac tttctccata ctttaaaggg gatgtcaaat 28320 tttagctcct ctcctgtacc cacaatcttc atgtctttct tcccagatga ccaagagagt 28380 ccggctcagt gactccttca accctgtcta cccctatgaa gatgaaagca cctcccaaca 28440 cccctttata aacccagggt ttatttcccc aaatggcttc acacaaagcc caaacggagt 28500 tcttacttta aaatgtttaa ccccactaac aaccacaggc ggatctctac agctaaaagt 28560 gggaggggga cttacagtgg atgacaccaa cggttttttg aaagaaaaca taagtgccac 28620 cacaccactc gttaagactg gtcactctat aggtttacca ctaggagccg gattgggaac 28680 gaatgaaaat aaactttgta tcaaattagg acaaggactt acattcaatt caaacaacat 28740 ttgcattgat gacaatatta acaccttatg gacaggagtc aaccccaccg aagccaactg 28800 tcaaatcatg aactccagtg aatctaatga ttgcaaatta attctaacac tagttaaaac 28860 tggagcacta gtcactgcat ttgtttatgt tataggagta tctaacaatt ttaatatgct 28920 aactacacac agaaatataa attttactgc agagctgttt ttcgattcta ctggtaattt 28980 actaactaga ctctcatccc tcaaaactcc acttaatcat aaatcaggac aaaacatggc 29040 tactggtgcc attactaatg ctaaaggttt catgcccagc acgactgcct atcctttcaa 29100 tgataattct agagaaaaag aaaactacat ttacggaact tgttactaca cagctagtga 29160 tcgcactgct tttcccattg acatatctgt catgcttaac cgaagagcaa taaatgacga 29220 gacatcatat tgtattcgta taacttggtc ctggaacaca ggagatgccc cagaggtgca 29280 aacctctgct acaaccctag tcacctcccc atttaccttt tactacatca gagaagacga 29340 ctgacaaata aagtttgcga tcgccaggcc caccatggga tggagctgta tcatcctctt 29400 cttggtagca acagctacag gtgtccactc ccaggtgcag ctgcagcagt ctggggctga 29460 actggcaaga cctggggcct cagtgaagat gtcctgcaag gcttctggct acacctttac 29520 taggtacacg atgcactggg taaaacagag gcctggacag ggtctggaat ggattggata 29580 cattaatcct agccgtggtt atactaatta caatcagaag ttcaaggaca aggccacatt 29640 gactacagac aaatcctcca gcacagccta catgcaactg agcagcctga catctgagga 29700 ctctgcagtc tattactgtg caagatatta tgatgatcat tactgccttg actactgggg 29760 ccaaggcacc actctcacag tctcctcagg tggcggtggc tcgggcggtg gtggatctgg 29820 tggcggcgga tctgatatcg tgctcactca gtctccagca atcatgtctg catctccagg 29880 ggagaaggtc accatgacct gcagtgccag ctcaagtgta agttacatga actggtacca 29940 gcagaagtca ggcacctccc ccaaaagatg gatttatgac acatccaaac tggcttctgg 30000 agtccctgct cacttcaggg gcagtgggtc tgggacctct tactctctca caatcagcgg 30060 catggaggct gaagatgctg ccacttatta ctgccagcag tggagtagta acccattcac 30120 gttcggctcg gggacaaagt tggaaataaa ccggggatcc gaacaaaaac tcatctcaga 30180 agaggatctg aatgctgtgg gccaggacac gcaggaggtc atcgtggtgc cacactcctt 30240 gccctttaag gtggtggtga tctcagccat cctggccctg gtggtgctca ccatcatctc 30300 ccttatcatc ctcatcatgc tttggcagaa gaagccacgt ggttcaatcc ctaaccctct 30360 cctcggtctc gatggaagcg gagctactaa cttcagcctg ctgaagcagg ctggagacgt 30420 ggaggagaac cctggacctg gccacacacg gaggcaggga acatcaccat ccaagtgtcc 30480 atacctcaat ttctttcagc tcttggtgct ggctggtctt tctcacttct gttcaggtgt 30540 tatccacgtg accaaggaag tgaaagaagt ggcaacgctg tcctgtggtc acaatgtttc 30600 tgttgaagag ctggcacaaa ctcgcatcta ctggcaaaag gagaagaaaa tggtgctgac 30660 tatgatgtct ggggacatga atatatggcc cgagtacaag aaccggacca tctttgatat 30720 cactaataac ctctccattg tgatcctggc tctgcgccca tctgacgagg gcacatacga 30780 gtgtgttgtt ctgaagtatg aaaaagacgc tttcaagcgg gaacacctgg ctgaagtgac 30840 gttatcagtc aaagctgact tccctacacc tagtatatct gactttgaaa ttccaacttc 30900 taatattaga aggataattt gctcaacctc tggaggtttt ccagagcctc acctctcctg 30960 gttggaaaat ggagaagaat taaatgccat caacacaaca gtttcccaag atcctgaaac 31020 tgagctctat gctgttagca gcaaactgga tttcaatatg acaaccaacc acagcttcat 31080 gtgtctcatc aagtatggac atttaagagt gaatcagacc ttcaactgga atacaaccaa 31140 gcaagagcat tttcctgata acctgctccc atcctgggcc attaccttaa tctcagtaaa 31200 tggaattttt gtgatatgct gcctgaccta ctgctttgcc ccaagatgca gagagagaag 31260 gaggaatgag agattgagaa gggaaagtgt acgccctgta taagctagct tgactgactg 31320 agatacagcg taccttcagc tcacagacat gataagatac attgatgagt ttggacaaac 31380 cacaactaga atgcagtgaa aaaaatgctt tatttgtgaa atttgtgatg ctattgcttt 31440 atttgtaacc attataagct gcaataaaca agttaacaac aacaattgca ttcattttat 31500 gtttcaggtt cagggggagg tgtgggaggt tttttaaagc aagtaaaacc tctacaaatg 31560 tggtagtcgt cagctatcct gcaggaactt gtttatttga aaatcaattc acaaaatccg 31620 agtagttatt ttgcctcccc cttcccattt aacagaatac accaatctct ccccacgcac 31680 agctttaaac atttggatac cattagatat agacatggtt ttagattcca cattccaaac 31740 agtttcagag cgagccaatc tggggtcagt gatagataaa aatccatcgg gatagtcttt 31800 taaagcgctt tcacagtcca actgctgcgg atgcgactcc ggagtctgga tcacggtcat 31860 ctggaagaag aacgatggga atcataatcc gaaaacggta tcggacgatt gtgtctcatc 31920 aaacccacaa gcagccgctg tctgcgtcgc tccgtgcgac tgctgtttat gggatcaggg 31980 tccacagtgt cctgaagcat gattttaata gcccttaaca tcaactttct ggtgcgatgc 32040 gcgcagcaac gcattctgat ttcactcaaa tctttgcagt aggtacaaca cattattaca 32 100 atattgttta ataaaccata attaaaagcg ctccagccaa aactcatatc tgatataatc 32160 gcccctgcat gaccatcata ccaaagttta atataaatta aatgacgttc cctcaaaaac 32220 acactaccca catacatgat ctcttttggc atgtgcatat taacaatctg tctgtaccat 32280 ggacaacgtt ggttaatcat gcaacccaat ataaccttcc ggaaccacac tgccaacacc 32340 gctcccccag ccatgcattg aagtgaaccc tgctgattac aatgacaatg aagaacccaa 32400 ttctctcgac cgtgaatcac ttgagaatga aaaatatcta tagtggcaca acatagacat 32460 aaatgcatgc atcttctcat aatttttaac tcctcaggat ttagaaacat atcccaggga 32520 ataggaagct cttgcagaac agtaaagctg gcagaacaag gaagaccacg aacacaactt 32580 acactatgca tagtcatagt atcacaatct ggcaacagcg ggtggtcttc agtcatagaa 32640 gctcgggttt cattttcctc acaacgtggt aactgggctc tggtgtaagg gtgatgtctg 32700 gcgcatgatg tcgagcgtgc gcgcaacctt gtcataatgg agttgcttcc tgacattctc 32760 gtattttgta tagcaaaacg cggccctggc agaacacact cttcttcgcc ttctatcctg 32820 ccgcttagcg tgttccgtgt gatagttcaa gtacaaccac actcttaagt tggtcaaaag 32880 aatgctggct tcagttgtaa tcaaaactcc atcgcatcta atcgttctga ggaaatcatc 32940 caagcaatgc aactggattg tgtttcaagc aggagaggag agggaagaga cggaagaacc 33000 atgttaattt ttattccaaa cgatctcgca gtacttcaaa ttgtagatcg cgcagatggc 33060 atctctcgcc cccactgtgt tggtgaaaaa gcacagctag atcaaaagaa atgcgatttt 33120 caaggtgctc aacggtggct tccagcaaag cctccacgcg cacatccaag aacaaaagaa 33180 taccaaaaga aggagcattt tctaactcct caatcatcat attacattcc tgcaccattc 33240 ccagataatt ttcagctttc cagccttgaa ttattcgtgt cagttcttgt ggtaaatcca 33300 atccacacat tacaaacagg tcccggaggg cgccctccac caccattctt aaacacaccc 33360 tcataatgac aaaatatctt gctcctgtgt cacctgtagc gaattgagaa tggcaacatc 33420 aattgacatg cccttggctc taagttcttc tttaagttct agttgtaaaa actctctcat 33480 attatcacca aactgcttag ccagaagccc cccgggaaca agagcagggg acgctacagt 33540 gcagtacaag cgcagacctc cccaattggc tccagcaaaa acaagattgg aataagcata 33600 ttgggaaccg ccagtaatat catcgaagtt gctggaaata taatcaggca gagtttcttg 33660 taaaaattga ataaaagaaa aatttgccaa aaaaacattc aaaacctctg ggatgcaaat 33720 gcaataggtt accgcgctgc gctccaacat tgttagtttt gaattagtct gcaaaaataa 33780 aaaaaaaaac aagcgtcata tcatagtagc ctgacgaaca gatggataaa tcagtctttc 33840 catcacaaga caagccacag ggtctccagc tcgaccctcg taaaacctgt catcatgatt 33900 aaacaacagc accgaaagtt cctcgcggtg accagcatga ataattcttg atgaagcata 33960 caatccagac atgttagcat cagttaacga gaaaaaacag ccaacatagc ctttgggtat 34020 aattatgctt aatcgtaagt atagcaaagc cacccctcgc ggatacaaag taaaaggcac 34080 aggagaataa aaaatataat tatttctctg ctgctgttca ggcaacgtcg cccccggtcc 34 140 ctctaaatac acatacaaag cctcatcagc catggcttac cagacaaagt acagcgggca 34200 cacaaagcac aagctctaaa gtgactctcc aacctctcca caatatatat atacacaagc 34260 cctaaactga cgtaatggga gtaaagtgta aaaaatcccg ccaaacccaa cacacacccc 34320 gaaactgcgt caccagggaa aagtacagtt tcacttccgc aatcccaaca ggcgtaactt 34380 cctctttctc acggtacgtg atatcccact aacttgcaac gtcattttcc cacggtcgca 34440 ccgccccttt tagccgttaa ccccacagcc aatcaccaca cgatccacac tttttaaaat 34500 cacctcattt acatattggc accattccat ctataaggta tattatatag ataga 34555 <210> 102 <211> 33595 <212> DNA <213> Artificial Sequence <220> <223> NG-420 virus genome sequence comprising a transgene cassette encoding a membrane-anchored chimeric form of the anti-human CD3e scFv inserted in the region BY <400> 102 tctatctata taatatacct tatagatgga atggtgccaa tatgtaaatg aggtgatttt 60 aaaaagtgtg gatcgtgtgg tgattggctg tggggttaac ggctaaaagg ggcggtgcga 120 ccgtgggaaa atgacgtttt gtgggggtgg agtttttttg caagttgtcg cgggaaatgt 180 gacgcataaa aaggcttttt tctcacggaa ctacttagtt ttcccacggt atttaacagg 240 aaatgaggta gttttgaccg gatgcaagtg aaaattgttg attttcgcgc gaaaactgaa 300 tgaggaagtg tttttctgaa taatgtggta tttatggcag ggtggagtat ttgttcaggg 360 ccaggtagac tttgacccat tacgtggagg tttcgattac cgtgtttttt acctgaattt 420 ccgcgtaccg tgtcaaagtc ttctgttttt acgtaggtgt cagctgatcg ctagggtatt 480 tatacctcag ggtttgtgtc aagaggccac tcttgagtgc cagcgagaag agttttctcc 540 tctgcgccgg cagtttaata ataaaaaaat gagagatttg cgatttctgc ctcaggaaat 600 aatctctgct gagactggaa atgaaatatt ggagcttgtg gtgcacgccc tgatgggaga 660 cgatccggag ccacctgtgc agctttttga gcctcctacg cttcaggaac tgtatgattt 720 agaggtagag ggatcggagg attctaatga ggaagctgta aatggctttt ttaccgattc 780 tatgctttta gctgctaatg aagggttaga attagatccg cctttggaca cttttgatac 840 tccaggggta attgtggaaa gcggtacagg tgtaagaaaa ttacctgatt tgagttccgt 900 ggactgtgat ttgcactgct atgaagacgg gtttcctccg agtgatgagg aggaccatga 960 aaaggagcag tccatgcaga ctgcagcggg tgagggagtg aaggctgcca atgttggttt 1020 tcagttggat tgcccggagc ttcctggaca tggctgtaag tcttgtgaat ttcacaggaa 1080 aaatactgga gtaaaggaac tgttatgttc gctttgttat atgagaacgc actgccactt 1140 tatttacagt aagtgtgttt aagttaaaat ttaaaggaat atgctgtttt tcacatgtat 1200 attgagtgtg agttttgtgc ttcttattat aggtcctgtg tctgatgctg atgaatcacc 1260 atctcctgat tctactacct cacctcctga gattcaagca cctgttcctg tggacgtgcg 1320 caagcccatt cctgtgaagc ttaagcctgg gaaacgtcca gcagtggaaa aacttgagga 1380 cttgttacag ggtggggacg gacctttgga cttgagtaca cggaaacgtc caagacaata 1440 agtgttccat atccgtgttt acttaaggtg acgtcaatat ttgtgtgaca gtgcaatgta 1500 ataaaaatat gttaactgtt cactggtttt tattgctttt tgggcgggga ctcaggtata 1560 taagtagaag cagacctgtg tggttagctc ataggagctg gctttcatcc atggaggttt 1620 gggccatttt ggaagacctt aggaagacta ggcaactgtt agagaacgct tcggacggag 1680 tctccggttt ttggagattc tggttcgcta gtgaattagc tagggtagtt tttaggataa 1740 aacaggacta taaacaagaa tttgaaaagt tgttggtaga ttgcccagga ctttttgaag 1800 ctcttaattt gggccatcag gttcacttta aagaaaaagt tttatcagtt ttagactttt 1860 caaccccagg tagaactgct gctgctgtgg cttttcttac ttttatatta gataaatgga 1920 tcccgcagac tcatttcagc aggggatacg ttttggattt catagccaca gcattgtgga 1980 gaacatggaa ggttcgcaag atgaggacaa tcttaggtta ctggccagtg cagcctttgg 2040 gtgtagcggg aatcctgagg catccaccgg tcatgccagc ggttctggag gaggaacagc 2100 aagaggacaa cccgagagcc ggcctggacc ctccagtgga ggaggcggag tagctgactt 2160 gtctcctgaa ctgcaacggg tgcttactgg atctacgtcc actggacggg ataggggcgt 2220 taagagggag agggcatcta gtggtactga tgctagatct gagttggctt taagtttaat 2280 gagtcgcaga cgtcctgaaa ccatttggtg gcatgaggtt cagaaagagg gaagggatga 2340 agtttctgta ttgcaggaga aatattcact ggaacaggtg aaaacatgtt ggttggagcc 2400 tgaggatgat tgggaggtgg ccattaaaaa ttatgccaag atagctttga ggcctgataa 2460 acagtataag attactagac ggattaatat ccggaatgct tgttacatat ctggaaatgg 2520 ggctgaggtg gtaatagata ctcaagacaa ggcagttatt agatgctgca tgatggatat 2580 gtggcctggg gtagtcggta tggaagcagt aacttttgta aatgttaagt ttaggggaga 2640 tggttataat ggaatagtgt ttatggccaa taccaaactt atattgcatg gttgtagctt 2700 ttttggtttc aacaatacct gtgtagatgc ctggggacag gttagtgtac ggggatgtag 2760 tttctatgcg tgttggattg ccacagctgg cagaaccaag agtcaattgt ctctgaagaa 2820 atgcatattt caaagatgta acctgggcat tctgaatgaa ggcgaagcaa gggtccgcca 2880 ctgcgcttct acagatactg gatgttttat tttgattaag ggaaatgcca gcgtaaagca 2940 taacatgatt tgcggtgctt ccgatgagag gccttatcaa atgctcactt gtgctggtgg 3000 gcattgtaat atgctggcta ctgtgcatat tgtttcccat caacgcaaaa aatggcctgt 3060 ttttgatcac aatgtgatga cgaagtgtac catgcatgca ggtgggcgta gaggaatgtt 3120 tatgccttac cagtgtaaca tgaatcatgt gaaagtgttg ttggaaccag atgccttttc 3180 cagaatgagc ctaacaggaa tttttgacat gaacatgcaa atctggaaga tcctgaggta 3240 tgatgatacg agatcgaggg tacgcgcatg cgaatgcgga ggcaagcatg ccaggttcca 3300 gccggtgtgt gtagatgtga ctgaagatct cagaccggat catttggtta ttgcccgcac 3360 tggagcagag ttcggatcca gtggagaaga aactgactaa ggtgagtatt gggaaaactt 3420 tggggtggga ttttcagatg gacagattga gtaaaaattt gttttttctg tcttgcagct 3480 gtcatgagtg gaaacgcttc ttttaagggg ggagtcttca gcccttatct gacagggcgt 3540 ctcccatcct gggcaggagt tcgtcagaat gttatgggat ctactgtgga tggaagaccc 3600 gtccaacccg ccaattcttc aacgctgacc tatgctactt taagttcttc acctttggac 3660 gcagctgcag ctgccgccgc cgcttctgtt gccgctaaca ctgtgcttgg aatgggttac 3720 tatggaagca tcatggctaa ttccacttcc tctaataacc cttctaccct gactcaggac 3780 aagttacttg tccttttggc ccagctggag gctttgaccc aacgtctggg tgaactttct 3840 cagcaggtgg tcgagttgcg agtacaaact gagtctgctg tcggcacggc aaagtctaaa 3900 taaaaaaatc ccagaatcaa tgaataaata aacaagcttg ttgttgattt aaaatcaagt 3960 gtttttattt catttttcgc gcacggtatg ccctagacca ccgatctcta tcattgagaa 4020 ctcggtggat tttttccagg atcctataga ggtgggattg aatgtttaga tacatgggca 4080 ttaggccgtc tttggggtgg agatagctcc attgaaggga ttcatgctcc ggggtagtgt 4140 tgtaaatcac ccagtcataa caaggtcgca gtgcatggtg ttgcacaata tcttttagaa 4200 gtaggctgat tgccacagat aagcccttgg tgtaggtgtt tacaaaccgg ttgagctggg 4260 atgggtgcat tcggggtgaa attatgtgca ttttggattg gatttttaag ttggcaatat 4320 tgccgccaag atcccgtctt gggttcatgt tatgaaggac caccaagacg gtgtatccgg 4380 tacatttagg aaatttatcg tgcagcttgg atggaaaagc gtggaaaaat ttggagacac 4440 ccttgtgtcc tccaagattt tccatgcact catccatgat aatagcaatg gggccgtggg 4500 cagcggcgcg ggcaaacacg ttccgtgggt ctgacacatc atagttatgt tcctgagtta 4560 aatcatcata agccatttta atgaatttgg ggcggagagt accagattgg ggtatgaatg 4620 ttccttcggg ccccggagca tagttcccct cacagatttg catttcccaa gctttcagtt 4680 ccgagggtgg aatcatgtcc acctgggggg ctatgaaaaa caccgtttct ggggcggggg 4740 tgattaattg tgatgatagc aaatttctga gcaattgaga tttgccacat ccggtggggc 4800 cataaatgat tccgattacg ggttgcaggt ggtagtttag ggaacggcaa ctgccgtctt 4860 ctcgaagcaa gggggccacc tcgttcatca tttcccttac atgcatattt tcccgcacca 4920 aatccattag gaggcgctct cctcctagtg atagaagttc ttgtagtgag gaaaagtttt 4980 tcagcggttt cagaccgtca gccatgggca ttttggagag agtttgctgc aaaagttcta 5040 gtctgttcca cagttcagtg atgtgttcta tggcatctcg atccagcaga cctcctcgtt 5100 tcgcgggttt ggacggctcc tggaataggg tatgagacga tgggcgtcca gcgctgccag 5160 ggttcggtcc ttccagggtc tcagtgttcg agtcagggtt gtttccgtca cagtgaaggg 5220 gtgtgcgcct gcttgggcgc ttgccagggt gcgcttcaga ctcatcctgc tggtcgaaaa 5280 cttctgtcgc ttggcgccct gtatgtcggc caagtagcag tttaccatga gttcgtagtt 5340 gagcgcctcg gctgcgtggc ctttggcgcg gagcttacct ttggaagttt tcttgcatac 5400 cgggcagtat aggcatttca gcgcatacaa cttgggcgca aggaaaacgg attctgggga 5460 gtatgcatct gcgccgcagg aggcgcaaac agtttcacat tccaccagcc aggttaaatc 5520 cggttcattg gggtcaaaaa caagttttcc gccatatttt ttgatgcgtt tcttaccttt 5580 ggtctccatg agttcgtgtc ctcgttgagt gacaaacagg ctgtccgtgt ccccgtagac 5640 tgattttaca ggcctcttct ccagtggagt gcctcggtct tcttcgtaca ggaactctga 5700 ccactctgat acaaaggcgc gcgtccaggc cagcacaaag gaggctatgt gggaggggta 5760 gcgatcgttg tcaaccaggg ggtccacctt ttccaaagta tgcaaacaca tgtcaccctc 5820 ttcaacatcc aggaatgtga ttggcttgta ggtgtatttc acgtgacctg gggtccccgc 5880 tgggggggta taaaaggggg cggttctttg ctcttcctca ctgtcttccg gatcgctgtc 5940 caggaacgtc agctgttggg gtaggtattc cctctcgaag gcgggcatga cctctgcact 6000 caggttgtca gtttctaaga acgaggagga tttgatattg acagtgccgg ttgagatgcc 6060 tttcatgagg ttttcgtcca tctggtcaga aaacacaatt tttttattgt caagtttggt 6120 ggcaaatgat ccatacaggg cgttggataa aagtttggca atggatcgca tggtttggtt 6180 cttttccttg tccgcgcgct ctttggcggc gatgttgagt tggacatact cgcgtgccag 6240 gcacttccat tcggggaaga tagttgttaa ttcatctggc acgattctca cttgccaccc 6300 tcgattatgc aaggtaatta aatccacact ggtggccacc tcgcctcgaa ggggttcatt 6360 ggtccaacag agcctacctc ctttcctaga acagaaaggg ggaagtgggt ctagcataag 6420 ttcatcggga gggtctgcat ccatggtaaa gattcccgga agtaaatcct tatcaaaata 6480 gctgatggga gtggggtcat ctaaggccat ttgccattct cgagctgcca gtgcgcgctc 6540 atatgggtta aggggactgc cccatggcat gggatgggtg agtgcagagg catacatgcc 6600 acagatgtca tagacgtaga tgggatcctc aaagatgcct atgtaggttg gatagcatcg 6660 cccccctctg atacttgctc gcacatagtc atatagttca tgtgatggcg ctagcagccc 6720 cggacccaag ttggtgcgat tgggtttttc tgttctgtag acgatctggc gaaagatggc 6780 gtgagaattg gaagagatgg tgggtctttg aaaaatgttg aaatgggcat gaggtagacc 6840 tacagagtct ctgacaaagt gggcataaga ttcttgaagc ttggttacca gttcggcggt 6900 gacaagtacg tctagggcgc agtagtcaag tgtttcttga atgatgtcat aacctggttg 6960 gtttttcttt tcccacagtt cgcggttgag aaggtattct tcgcgatcct tccagtactc 7020 ttctagcgga aacccgtctt tgtctgcacg gtaagatcct agcatgtaga actgattaac 7080 tgccttgtaa gggcagcagc ccttctctac gggtagagag tatgcttgag cagcttttcg 7140 tagcgaagcg tgagtaaggg caaaggtgtc tctgaccatg actttgagga attggtattt 7200 gaagtcgatg tcgtcacagg ctccctgttc ccagagttgg aagtctaccc gtttcttgta 7260 ggcggggttg ggcaaagcga aagtaacatc attgaagaga atcttgccgg ccctgggcat 7320 gaaattgcga gtgatgcgaa aaggctgtgg tacttccgct cggttattga taacctgggc 7380 agctaggacg atctcgtcga aaccgttgat gttgtgtcct acgatgtata attctatgaa 7440 acgcggcgtg cctctgacgt gaggtagctt actgagctca tcaaaggtta ggtctgtggg 7500 gtcagataag gcgtagtgtt cgagagccca ttcgtgcagg tgaggattcg ctttaaggaa 7560 ggaggaccag aggtccactg ccagtgctgt ttgtaactgg tcccggtact gacgaaaatg 7620 ccgtccgact gccatttttt ctggggtgac gcaatagaag gtttgggggt cctgccgcca 7680 gcgatcccac ttgagtttta tggcgaggtc ataggcgatg ttgacgagcc gctggtctcc 7740 agagagtttc atgaccagca tgaaggggat tagctgcttg ccaaaggacc ccatccaggt 7800 gtaggtttcc acatcgtagg tgagaaagag cctttctgtg cgaggatgag agccaatcgg 7860 gaagaactgg atctcctgcc accagttgga ggaatggctg ttgatgtgat ggaagtagaa 7920 ctccctgcga cgcgccgagc attcatgctt gtgcttgtac agacggccgc agtagtcgca 7980 gcgttgcacg ggttgtatct cgtgaatgag ttgtacctgg cttcccttga cgagaaattt 8040 cagtgggaag ccgaggcctg gcgattgtat ctcgtgcttt actatgttgt ctgcatcggc 8100 ctgttcatct tctgtctcga tggtggtcat gctgacgagc cctcgcggga ggcaagtcca 8160 gacctcggcg cggcaggggc ggagctcgag gacgagagcg cgcaggctgg agctgtccag 8220 ggtcctgaga cgctgcggac tcaggttagt aggcagtgtc aggagattaa cttgcatgat 8280 cttttggagg gcgtgcggga ggttcagata gtacttgatc tcaacgggtc cgttggtgga 8340 gatgtcgatg gcttgcaggg ttccgtgtcc cttgggcgct accaccgtgc ccttgttttt 8400 cattttggac ggcggtggct ctgttgcttc ttgcatgttt agaagcggtg tcgagggcgc 8460 gcaccgggcg gcaggggcgg ctcgggaccc ggcggcatgg ctggcagtgg tacgtcggcg 8520 ccgcgcgcgg gtaggttctg gtactgcgcc ctgagaagac tcgcatgcgc gacgacgcgg 8580 cggttgacat cctggatctg acgcctctgg gtgaaagcta ccggccccgt gagcttgaac 8640 ctgaaagaga gttcaacaga atcaatctcg gtatcgttga cggcggcttg cctaaggatt 8700 tcttgcacgt caccagagtt gtcctggtag gcgatctccg ccatgaactg ctcgatctct 8760 tcctcttgaa gatctccgcg gcccgctctc tcgacggtgg ccgcgaggtc gttggagatg 8820 cgcccaatga gttgagagaa tgcattcatg cccgcctcgt tccagacgcg gctgtagacc 8880 acggccccca cgggatctct cgcgcgcatg accacctggg cgaggttgag ctccacgtgg 8940 cgggtgaaga ccgcatagtt gcataggcgc tggaaaaggt agttgagtgt ggtggcgatg 9000 tgctcggtga cgaagaaata catgatccat cgtctcagcg gcatctcgct gacatcgccc 9060 agagcttcca agcgctccat ggcctcgtag aagtccacgg caaaattaaa aaactgggag 9120 tttcgcgcgg acacggtcaa ctcctcttcc agaagacgga taagttcggc gatggtggtg 9180 cgcacctcgc gctcgaaagc ccctgggatt tcttcctcaa tctcttcttc ttccactaac 9240 atctcttcct cttcaggtgg ggctgcagga ggagggggaa cgcggcgacg ccggcggcgc 9300 acgggcagac ggtcgatgaa tctttcaatg acctctccgc ggcggcggcg catggtttca 9360 gtgacggcgc ggccgttctc gcgcggtcgc agagtaaaaa caccgccgcg catctcctta 9420 aagtggtgac tgggaggttc tccgtttggg agggagaggg cgctgattat acattttatt 9480 aattggcccg tagggactgc acgcagagat ctgatcgtgt caagatccac gggatctgaa 9540 aacctttcga cgaaagcgtc taaccagtca cagtcacaag gtaggctgag tacggcttct 9600 tgtgggcggg ggtggttatg tgttcggtct gggtcttctg tttcttcttc atctcgggaa 9660 ggtgagacga tgctgctggt gatgaaatta aagtaggcag ttctaagacg gcggatggtg 9720 gcgaggagca ccaggtcttt gggtccggct tgctggatac gcaggcgatt ggccattccc 9780 caagcattat cctgacatct agcaagatct ttgtagtagt cttgcatgag ccgttctacg 9840 ggcacttctt cctcacccgt tctgccatgc atacgtgtga gtccaaatcc gcgcattggt 9900 tgtaccagtg ccaagtcagc tacgactctt tcggcgagga tggcttgctg tacttgggta 9960 agggtggctt gaaagtcatc aaaatccaca aagcggtggt aagctcctgt attaatggtg 10020 taagcacagt tggccatgac tgaccagtta actgtctggt gaccagggcg cacgagctcg 10080 gtgtatttaa ggcgcgaata ggcgcgggtg tcaaagatgt aatcgttgca ggtgcgcacc 10140 agatactggt accctataag aaaatgcggc ggtggttggc ggtagagagg ccatcgttct 10200 gtagctggag cgccaggggc gaggtcttcc aacataaggc ggtgatagcc gtagatgtac 10260 ctggacatcc aggtgattcc tgcggcggta gtagaagccc gaggaaactc gcgtacgcgg 10320 ttccaaatgt tgcgtagcgg catgaagtag ttcattgtag gcacggtttg accagtgagg 10380 cgcgcgcagt cattgatgct ctatagacac ggagaaaatg aaagcgttca gcgactcgac 10440 tccgtagcct ggaggaacgt gaacgggttg ggtcgcggtg taccccggtt cgagacttgt 10500 actcgagccg gccggagccg cggctaacgt ggtattggca ctcccgtctc gacccagcct 10560 acaaaaatcc aggatacgga atcgagtcgt tttgctggtt tccgaatggc agggaagtga 10620 gtcctatttt ttttttttgc cgctcagatg catcccgtgc tgcgacagat gcgcccccaa 10680 caacagcccc cctcgcagca gcagcagcag caatcacaaa aggctgtccc tgcaactact 10740 gcaactgccg ccgtgagcgg tgcgggacag cccgcctatg atctggactt ggaagagggc 10800 gaaggactgg cacgtctagg tgcgccttca cccgagcggc atccgcgagt tcaactgaaa 10860 aaagattctc gcgaggcgta tgtgccccaa cagaacctat ttagagacag aagcggcgag 10920 gagccggagg agatgcgagc ttcccgcttt aacgcgggtc gtgagctgcg tcacggtttg 10980 gaccgaagac gagtgttgcg ggacgaggat ttcgaagttg atgaaatgac agggatcagt 11040 cctgccaggg cacacgtggc tgcagccaac cttgtatcgg cttacgagca gacagtaaag 11 100 gaagagcgta acttccaaaa gtcttttaat aatcatgtgc gaaccctgat tgcccgcgaa 11160 gaagttaccc ttggtttgat gcatttgtgg gatttgatgg aagctatcat tcagaaccct 11220 actagcaaac ctctgaccgc ccagctgttt ctggtggtgc aacacagcag agacaatgag 11280 gctttcagag aggcgctgct gaacatcacc gaacccgagg ggagatggtt gtatgatctt 11340 atcaacattc tacagagtat catagtgcag gagcggagcc tgggcctggc cgagaaggtg 11400 gctgccatca attactcggt tttgagcttg ggaaaatatt acgctcgcaa aatctacaag 11460 actccatacg ttcccataga caaggaggtg aagatagatg ggttctacat gcgcatgacg 11520 ctcaaggtct tgaccctgag cgatgatctt ggggtgtatc gcaatgacag aatgcatcgc 11580 gcggttagcg ccagcaggag gcgcgagtta agcgacaggg aactgatgca cagtttgcaa 11640 agagctctga ctggagctgg aaccgagggt gagaattact tcgacatggg agctgacttg 11700 cagtggcagc ctagtcgcag ggctctgagc gccgcgacgg caggatgtga gcttccttac 11760 atagaagagg cggatgaagg cgaggaggaa gagggcgagt acttggaaga ctgatggcac 11820 aacccgtgtt ttttgctaga tggaacagca agcaccggat cccgcaatgc gggcggcgct 11880 gcagagccag ccgtccggca ttaactcctc ggacgattgg acccaggcca tgcaacgtat 11940 catggcgttg acgactcgca accccgaagc ctttagacag caaccccagg ccaaccgtct 12000 atcggccatc atggaagctg tagtgccttc ccgctctaat cccactcatg agaaggtcct 12060 ggccatcgtg aacgcgttgg tggagaacaa agctattcgt ccagatgagg ccggactggt 12120 atacaacgct ctcttagaac gcgtggctcg ctacaacagt agcaatgtgc aaaccaattt 12180 ggaccgtatg ataacagatg tacgcgaagc cgtgtctcag cgcgaaaggt tccagcgtga 12240 tgccaacctg ggttcgctgg tggcgttaaa tgctttcttg agtactcagc ctgctaatgt 12300 gccgcgtggt caacaggatt atactaactt tttaagtgct ttgagactga tggtatcaga 12360 agtacctcag agcgaagtgt atcagtccgg tcctgattac ttctttcaga ctagcagaca 12420 gggcttgcag acggtaaatc tgagccaagc ttttaaaaac cttaaaggtt tgtggggagt 12480 gcatgccccg gtaggagaaa gagcaaccgt gtctagcttg ttaactccga actcccgcct 12540 attattactg ttggtagctc ctttcaccga cagcggtagc atcgaccgta attcctattt 12600 gggttaccta ctaaacctgt atcgcgaagc catagggcaa agtcaggtgg acgagcagac 12660 ctatcaagaa attacccaag tcagtcgcgc tttgggacag gaagacactg gcagtttgga 12720 agccactctg aacttcttgc ttaccaatcg gtctcaaaag atccctcctc aatatgctct 12780 tactgcggag gaggagagga tccttagata tgtgcagcag agcgtgggat tgtttctgat 12840 gcaagagggg gcaactccga ctgcagcact ggacatgaca gcgcgaaata tggagcccag 12900 catgtatgcc agtaaccgac ctttcattaa caaactgctg gactacttgc acagagctgc 12960 cgctatgaac tctgattatt tcaccaatgc catcttaaac ccgcactggc tgcccccacc 13020 tggtttctac acgggcgaat atgacatgcc cgaccctaat gacggatttc tgtgggacga 13080 cgtggacagc gatgtttttt cacctctttc tgatcatcgc acgtggaaaa aggaaggcgg 13140 cgatagaatg cattcttctg catcgctgtc cggggtcatg ggtgctaccg cggctgagcc 13200 cgagtctgca agtccttttc ctagtctacc cttttctcta cacagtgtac gtagcagcga 13260 agtgggtaga ataagtcgcc cgagtttaat gggcgaagag gagtatctaa acgattcctt 13320 gctcagaccg gcaagagaaa aaaatttccc aaacaatgga atagaaagtt tggtggataa 13380 aatgagtaga tggaagactt atgctcagga tcacagagac gagcctggga tcatggggat 13440 tacaagtaga gcgagccgta gacgccagcg ccatgacaga cagaggggtc ttgtgtggga 13500 cgatgaggat tcggccgatg atagcagcgt gctggacttg ggtgggagag gaaggggcaa 13560 cccgtttgct catttgcgcc ctcgcttggg tggtatgttg taaaaaaaaa taaaaaaaaa 13620 actcaccaag gccatggcga cgagcgtacg ttcgttcttc tttattatct gtgtctagta 13680 taatgaggcg agtcgtgcta ggcggagcgg tggtgtatcc ggagggtcct cctccttcgt 13740 acgagagcgt gatgcagcag cagcaggcga cggcggtgat gcaatcccca ctggaggctc 13800 cctttgtgcc tccgcgatac ctggcaccta cggagggcag aaacagcatt cgttattcgg 13860 aactggcacc tcagtacgat accaccaggt tgtatctggt ggacaacaag tcggcggaca 13920 ttgcttctct gaactatcag aatgaccaca gcaacttctt gaccacggtg gtgcaaaaca 13980 atgactttac ccctacggaa gccagcaccc agaccattaa ctttgatgaa cgatcgcggt 14040 ggggcggtca gctaaagacc atcatgcata ctaacatgcc aaacgtgaac gagtatatgt 14100 ttagtaacaa gttcaaagcg cgtgtgatgg tgtccagaaa acctcccgac ggtgctgcag 14160 ttggggatac ttatgatcac aagcaggata ttttgaaata tgagtggttc gagtttactt 14220 tgccagaagg caacttttca gttactatga ctattgattt gatgaacaat gccatcatag 14280 ataattactt gaaagtgggt agacagaatg gagtgcttga aagtgacatt ggtgttaagt 14340 tcgacaccag gaacttcaag ctgggatggg atcccgaaac caagttgatc atgcctggag 14400 tgtatacgta tgaagccttc catcctgaca ttgtcttact gcctggctgc ggagtggatt 14460 ttaccgagag tcgtttgagc aaccttcttg gtatcagaaa aaaacagcca tttcaagagg 14520 gttttaagat tttgtatgaa gatttagaag gtggtaatat tccggccctc ttggatgtag 14580 atgcctatga gaacagtaag aaagaacaaa aagccaaaat agaagctgct acagctgctg 14640 cagaagctaa ggcaaacata gttgccagcg actctacaag ggttgctaac gctggagagg 14700 tcagaggaga caattttgcg ccaacacctg ttccgactgc agaatcatta ttggccgatg 14760 tgtctgaagg aacggacgtg aaactcacta ttcaacctgt agaaaaagat agtaagaata 14820 gaagctataa tgtgttggaa gacaaaatca acacagccta tcgcagttgg tatctttcgt 14880 acaattatgg cgatcccgaa aaaggagtgc gttcctggac attgctcacc acctcagatg 14940 tcacctgcgg agcagagcag gtctactggt cgcttccaga catgatgaag gatcctgtca 15000 ctttccgctc cactagacaa gtcagtaact accctgtggt gggtgcagag cttatgcccg 15060 tcttctcaaa gagcttctac aacgaacaag ctgtgtactc ccagcagctc cgccagtcca 15120 cctcgcttac gcacgtcttc aaccgctttc ctgagaacca gattttaatc cgtccgccgg 15180 cgcccaccat taccaccgtc agtgaaaacg ttcctgctct cacagatcac gggaccctgc 15240 cgttgcgcag cagtatccgg ggagtccaac gtgtgaccgt tactgacgcc agacgccgca 15300 cctgtcccta cgtgtacaag gcactgggca tagtcgcacc gcgcgtcctt tcaagccgca 15360 ctttctaaaa aaaaaaaaaa tgtccattct tatctcgccc agtaataaca ccggttgggg 15420 tctgcgcgct ccaagcaaga tgtacggagg cgcacgcaaa cgttctaccc aacatcctgt 15480 ccgtgttcgc ggacattttc gcgctccatg gggcgccctc aagggccgca ctcgcgttcg 15540 aaccaccgtc gatgatgtaa tcgatcaggt ggttgccgac gcccgtaatt atactcctac 15600 tgcgcctaca tctactgtgg atgcagttat tgacagtgta gtggctgacg ctcgcaacta 15660 tgctcgacgt aagagccggc gaaggcgcat tgccagacgc caccgagcta ccactgccat 15720 gcgagccgca agagctctgc tacgaagagc tagacgcgtg gggcgaagag ccatgcttag 15780 ggcggccaga cgtgcagctt cgggcgccag cgccggcagg tcccgcaggc aagcagccgc 15840 tgtcgcagcg gcgactattg ccgacatggc ccaatcgcga agaggcaatg tatactgggt 15900 gcgtgacgct gccaccggtc aacgtgtacc cgtgcgcacc cgtccccctc gcacttagaa 15960 gatactgagc agtctccgat gttgtgtccc agcggcgagg atgtccaagc gcaaatacaa 16020 ggaagaaatg ctgcaggtta tcgcacctga agtctacggc caaccgttga aggatgaaaa 16080 aaaaccccgc aaaatcaagc gggttaaaaa ggacaaaaaa gaagaggaag atggcgatga 16140 tgggctggcg gagtttgtgc gcgagtttgc cccacggcga cgcgtgcaat ggcgtgggcg 16200 caaagttcga catgtgttga gacctggaac ttcggtggtc tttacacccg gcgagcgttc 16260 aagcgctact tttaagcgtt cctatgatga ggtgtacggg gatgatgata ttcttgagca 16320 ggcggctgac cgattaggcg agtttgctta tggcaagcgt agtagaataa cttccaagga 16380 tgagacagtg tcgataccct tggatcatgg aaatcccacc cctagtctta aaccggtcac 16440 tttgcagcaa gtgttacccg taactccgcg aacaggtgtt aaacgcgaag gtgaagattt 16500 gtatcccact atgcaactga tggtacccaa acgccagaag ttggaggacg ttttggagaa 16560 agtaaaagtg gatccagata ttcaacctga ggttaaagtg agacccatta agcaggtagc 16620 gcctggtctg ggggtacaaa ctgtagacat taagattccc actgaaagta tggaagtgca 16680 aactgaaccc gcaaagccta ctgccacctc cactgaagtg caaacggatc catggatgcc 16740 catgcctatt acaactgacg ccgccggtcc cactcgaaga tcccgacgaa agtacggtcc 16800 agcaagtctg ttgatgccca attatgttgt acacccatct attattccta ctcctggtta 16860 ccgaggcact cgctactatc gcagccgaaa cagtacctcc cgccgtcgcc gcaagacacc 16920 tgcaaatcgc agtcgtcgcc gtagacgcac aagcaaaccg actcccggcg ccctggtgcg 16980 gcaagtgtac cgcaatggta gtgcggaacc tttgacactg ccgcgtgcgc gttaccatcc 17040 gagtatcatc acttaatcaa tgttgccgct gcctccttgc agatatggcc ctcacttgtc 17100 gccttcgcgt tcccatcact ggttaccgag gaagaaactc gcgccgtaga agagggatgt 17160 tgggacgcgg aatgcgacgc tacaggcgac ggcgtgctat ccgcaagcaa ttgcggggtg 17220 gttttttacc agccttaatt ccaattatcg ctgctgcaat tggcgcgata ccaggcatag 17280 cttccgtggc ggttcaggcc tcgcaacgac attgacattg gaaaaaaacg tataaataaa 17340 aaaaaaaaaa tacaatggac tctgacactc ctggtcctgt gactatgttt tcttagagat 17400 ggaagacatc aatttttcat ccttggctcc gcgacacggc acgaagccgt acatgggcac 17460 ctggagcgac atcggcacga gccaactgaa cgggggcgcc ttcaattgga gcagtatctg 17520 gagcgggctt aaaaattttg gctcaaccat aaaaacatac gggaacaaag cttggaacag 17580 cagtacagga caggcgctta gaaataaact taaagaccag aacttccaac aaaaagtagt 17640 cgatgggata gcttccggca tcaatggagt ggtagatttg gctaaccagg ctgtgcagaa 17700 aaagataaac agtcgtttgg acccgccgcc agcaacccca ggtgaaatgc aagtggagga 17760 agaaattcct ccgccagaaa aacgaggcga caagcgtccg cgtcccgatt tggaagagac 17820 gctggtgacg cgcgtagatg aaccgccttc ttatgaggaa gcaacgaagc ttggaatgcc 17880 caccactaga ccgatagccc caatggccac cggggtgatg aaaccttctc agttgcatcg 17940 acccgtcacc ttggatttgc cccctccccc tgctgctact gctgtacccg cttctaagcc 18000 tgtcgctgcc ccgaaaccag tcgccgtagc caggtcacgt cccgggggcg ctcctcgtcc 18060 aaatgcgcac tggcaaaata ctctgaacag catcgtgggt ctaggcgtgc aaagtgtaaa 18 120 acgccgtcgc tgcttttaat taaatatgga gtagcgctta acttgcctat ctgtgtatat 18180 gtgtcattac acgccgtcac agcagcagag gaaaaaagga agaggtcgtg cgtcgacgct 18240 gagttacttt caagatggcc accccatcga tgctgcccca atgggcatac atgcacatcg 18300 ccggacagga tgcttcggag tacctgagtc cgggtctggt gcagttcgcc cgcgccacag 18360 acacctactt caatctggga aataagttta gaaatcccac cgtagcgccg acccacgatg 18420 tgaccaccga ccgtagccag cggctcatgt tgcgcttcgt gcccgttgac cgggaggaca 18480 atacatactc ttacaaagtg cggtacaccc tggccgtggg cgacaacaga gtgctggata 18540 tggccagcac gttctttgac attaggggtg tgttggacag aggtcccagt ttcaaaccct 18600 attctggtac ggcttacaac tccctggctc ctaaaggcgc tccaaataca tctcagtgga 18660 ttgcagaagg tgtaaaaaat acaactggtg aggaacacgt aacagaagag gaaaccaata 18720 ctactactta cacttttggc aatgctcctg taaaagctga agctgaaatt acaaaagaag 18780 gactcccagt aggtttggaa gtttcagatg aagaaagtaa accgatttat gctgataaaa 18840 catatcagcc agaacctcag ctgggagatg aaacttggac tgaccttgat ggaaaaaccg 18900 aaaagtatgg aggcagggct ctcaaacccg atactaagat gaaaccatgc tacgggtcct 18960 ttgccaaacc tactaatgtg aaaggcggtc aggcaaaaca aaaaacaacg gagcagccaa 19020 atcagaaagt cgaatatgat atcgacatgg agttttttga tgcggcatcg cagaaaacaa 19080 acttaagtcc taaaattgtc atgtatgcag aaaatgtaaa tttggaaact ccagacactc 19140 atgtagtgta caaacctgga acagaagaca caagttccga agctaatttg ggacaacaat 19200 ctatgcccaa cagacccaac tacattggct tcagagataa ctttattgga cttatgtact 19260 ataacagtac tggtaacatg ggggtgctgg ctggtcaagc gtctcagtta aatgcagtgg 19320 ttgacttgca ggacagaaac acagaacttt cttaccaact cttgcttgac tctctgggcg 19380 acagaaccag atactttagc atgtggaatc aggctgtgga cagttatgat cctgatgtac 19440 gtgttattga aaatcatggt gtggaagatg aacttcccaa ctactgtttt ccactggacg 19500 gcataggtgt tccaacaacc agttacaaat caatagttcc aaatggagac aatgcgccta 19560 attggaagga acctgaagta aatggaacaa gtgagatcgg acagggtaat ttgtttgcca 19620 tggaaattaa ccttcaagcc aatctatggc gaagtttcct ttattccaat gtggctctat 19680 atctcccaga ctcgtacaaa tacaccccgt ccaatgtcac tcttccagaa aacaaaaaca 19740 cctacgacta catgaacggg cgggtggtgc cgccatctct agtagacacc tatgtgaaca 19800 ttggtgccag gtggtctctg gatgccatgg acaatgtcaa cccattcaac caccaccgta 19860 acgctggctt gcgttaccga tccatgcttc tgggtaacgg acgttatgtg cctttccaca 19920 tacaagtgcc tcaaaaattc ttcgctgtta aaaacctgct gcttctccca ggctcctaca 19980 cttatgagtg gaactttagg aaggatgtga acatggttct acagagttcc ctcggtaacg 20040 acctgcgggt agatggcgcc agcatcagtt tcacgagcat caacctctat gctacttttt 20100 tccccatggc tcacaacacc gcttccaccc ttgaagccat gctgcggaat gacaccaatg 20160 atcagtcatt caacgactac ctatctgcag ctaacatgct ctaccccatt cctgccaatg 20220 caaccaatat tcccatttcc attccttctc gcaactgggc ggctttcaga ggctggtcat 20280 ttaccagact gaaaaccaaa gaaactccct ctttggggtc tggatttgac ccctactttg 20340 tctattctgg ttctattccc tacctggatg gtaccttcta cctgaaccac acttttaaga 20400 aggtttccat catgtttgac tcttcagtga gctggcctgg aaatgacagg ttactatctc 20460 ctaacgaatt tgaaataaag cgcactgtgg atggcgaagg ctacaacgta gcccaatgca 20520 acatgaccaa agactggttc ttggtacaga tgctcgccaa ctacaacatc ggctatcagg 20580 gcttctacat tccagaagga tacaaagatc gcatgtattc atttttcaga aacttccagc 20640 ccatgagcag gcaggtggtt gatgaggtca attacaaaga cttcaaggcc gtcgccatac 20700 cctaccaaca caacaactct ggctttgtgg gttacatggc tccgaccatg cgccaaggtc 20760 aaccctatcc cgctaactat ccctatccac tcattggaac aactgccgta aatagtgtta 20820 cgcagaaaaa gttcttgtgt gacagaacca tgtggcgcat accgttctcg agcaacttca 20880 tgtctatggg ggcccttaca gacttgggac agaatatgct ctatgccaac tcagctcatg 20940 ctctggacat gacctttgag gtggatccca tggatgagcc caccctgctt tatcttctct 21000 tcgaagtttt cgacgtggtc agagtgcatc agccacaccg cggcatcatc gaggcagtct 21060 acctgcgtac accgttctcg gccggtaacg ctaccacgta agaagcttct tgcttcttgc 21120 aaatagcagc tgcaaccatg gcctgcggat cccaaaacgg ctccagcgag caagagctca 21180 gagccattgt ccaagacctg ggttgcggac cctatttttt gggaacctac gataagcgct 21240 tcccggggtt catggccccc gataagctcg cctgtgccat tgtaaatacg gccggacgtg 21300 agacgggggg agagcactgg ttggctttcg gttggaaccc acgttctaac acctgctacc 21360 tttttgatcc ttttggattc tcggatgatc gtctcaaaca gatttaccag tttgaatatg 21420 agggtctcct gcgccgcagc gctcttgcta ccaaggaccg ctgtattacg ctggaaaaat 21480 ctacccagac cgtgcagggt ccccgttctg ccgcctgcgg acttttctgc tgcatgttcc 21540 ttcacgcctt tgtgcactgg cctgaccgtc ccatggacgg aaaccccacc atgaaattgc 21600 taactggagt gccaaacaac atgcttcatt ctcctaaagt ccagcccacc ctgtgtgaca 21660 atcaaaaagc actctaccat tttcttaata cccattcgcc ttattttcgc tcccatcgta 21720 cacacatcga aagggccact gcgttcgacc gtatggatgt tcaataatga ctcatgtaaa 21780 caacgtgttc aataaacatc actttatttt tttacatgta tcaaggctct gcattactta 21840 tttatttaca agtcgaatgg gttctgacga gaatcagaat gacccgcagg cagtgatacg 21900 ttgcggaact gatacttggg ttgccacttg aattcgggaa tcaccaactt gggaaccggt 21960 atatcgggca ggatgtcact ccacagcttt ctggtcagct gcaaagctcc aagcaggtca 22020 ggagccgaaa tcttgaaatc acaattagga ccagtgcttt gagcgcgaga gttgcggtac 22080 accggattgc agcactgaaa caccatcagc gacggatgtc tcacgcttgc cagcacggtg 22140 ggatctgcaa tcatgcccac atccagatct tcagcattgg caatgctgaa cggggtcatc 22200 ttgcaggtct gcctacccat ggcgggcacc caattaggct tgtggttgca atcgcagtgc 22260 agggggatca gtatcatctt ggcctgatcc tgtctgattc ctggatacac ggctctcatg 22320 aaagcatcat attgcttgaa agcctgctgg gctttactac cctcggtata aaacatcccg 22380 caggacctgc tcgaaaactg gttagctgca cagccggcat cattcacaca gcagcgggcg 22440 tcattgttag ctatttgcac cacacttctg ccccagcggt tttgggtgat tttggttcgc 22500 tcgggattct cctttaaggc tcgttgtccg ttctcgctgg ccacatccat ctcgataatc 22560 tgctccttct gaatcataat attgccatgc aggcacttca gcttgccctc ataatcattg 22620 cagccatgag gccacaacgc acagcctgta cattcccaat tatggtgggc gatctgagaa 22680 aaagaatgta tcattccctg cagaaatctt cccatcatcg tgctcagtgt cttgtgacta 22740 gtgaaagtta actggatgcc tcggtgctcc tcgtttacgt actggtgaca gatgcgcttg 22800 tattgttcgt gttgctcagg cattagttta aaagaggttc taagttcgtt atccagcctg 22860 tacttctcca tcagcagaca catcacttcc atgcctttct cccaagcaga caccaggggc 22920 aagctaatcg gattcttaac agtgcaggca gcagctcctt tagccagagg gtcatcttta 22980 gcgatcttct caatgcttct tttgccatcc ttctcaacga tgcgcacggg cgggtagctg 23040 aaacccactg ctacaagttg cgcctcttct ctttcttctt cgctgtcttg actgatgtct 23100 tgcatgggga tatgtttggt cttccttggc ttctttttgg ggggtatcgg aggaggagga 23160 ctgtcgctcc gttccggaga cagggaggat tgtgacgttt cgctcaccat taccaactga 23220 ctgtcggtag aagaacctga ccccacacgg cgacaggtgt ttctcttcgg gggcagaggt 23280 ggaggcgatt gcgaagggct gcggtccgac ctggaaggcg gatgactggc agaacccctt 23340 ccgcgttcgg gggtgtgctc cctgtggcgg tcgcttaact gatttccttc gcggctggcc 23400 attgtgttct cctaggcaga gaaacaacag acatggaaac tcagccattg ctgtcaacat 23460 cgccacgagt gccatcacat ctcgtcctca gcgacgagga aaaggagcag agcttaagca 23520 ttccaccgcc cagtcctgcc accacctcta ccctagaaga taaggaggtc gacgcatctc 23580 atgacatgca gaataaaaaa gcgaaagagt ctgagacaga catcgagcaa gacccgggct 23640 atgtgacacc ggtggaacac gaggaagagt tgaaacgctt tctagagaga gaggatgaaa 23700 actgcccaaa acaacgagca gataactatc accaagatgc tggaaatagg gatcagaaca 23760 ccgactacct catagggctt gacggggaag acgcgctcct taaacatcta gcaagacagt 23820 cgctcatagt caaggatgca ttattggaca gaactgaagt gcccatcagt gtggaagagc 23880 tcagccgcgc ctacgagctt aacctctttt cacctcgtac tccccccaaa cgtcagccaa 23940 acggcacctg cgagccaaat cctcgcttaa acttttatcc agcttttgct gtgccagaag 24000 tactggctac ctatcacatc ttttttaaaa atcaaaaaat tccagtctcc tgccgcgcta 24060 atcgcacccg cgccgatgcc ctactcaatc tgggacctgg ttcacgctta cctgatatag 24120 cttccttgga agaggttcca aagatcttcg agggtctggg caataatgag actcgggccg 24180 caaatgctct gcaaaaggga gaaaatggca tggatgagca tcacagcgtt ctggtggaat 24 240 tggaaggcga taatgccaga ctcgcagtac tcaagcgaag catcgaggtc acacacttcg 24300 catatcccgc tgtcaacctg ccccctaaag tcatgacggc ggtcatggac cagttactca 24360 ttaagcgcgc aagtcccctt tcagaagaca tgcatgaccc agatgcctgt gatgagggta 24420 aaccagtggt cagtgatgag cagctaaccc gatggctggg caccgactct cccagggatt 24480 tggaagagcg tcgcaagctt atgatggccg tggtgctggt taccgtagaa ctagagtgtc 24540 tccgacgttt ctttaccgat tcagaaacct tgcgcaaact cgaagagaat ctgcactaca 24600 cttttagaca cggctttgtg cggcaggcat gcaagatatc taacgtggaa ctcaccaacc 24660 tggtttccta catgggtatt ctgcatgaga atcgcctagg acaaagcgtg ctgcacagca 24720 ccctgaaggg ggaagcccgc cgtgattaca tccgcgattg tgtctatctg tacctgtgcc 24780 acacgtggca aaccggcatg ggtgtatggc agcaatgttt agaagaacag aacttgaaag 24840 agcttgacaa gctcttacag aaatctctta aggttctgtg gacagggttc gacgagcgca 24900 ccgtcgcttc cgacctggca gacctcatct tcccagagcg tctcagggtt actttgcgaa 24960 acggattgcc tgactttatg agccagagca tgcttaacaa ttttcgctct ttcatcctgg 25020 aacgctccgg tatcctgccc gccacctgct gcgcactgcc ctccgacttt gtgcctctca 25080 cctaccgcga gtgccccccg ccgctatgga gtcactgcta cctgttccgt ctggccaact 25 140 atctctccta ccactcggat gtgatcgagg atgtgagcgg agacggcttg ctggagtgtc 25200 actgccgctg caatctgtgc acgccccacc ggtccctagc ttgcaacccc cagttgatga 25260 gcgaaaccca gataataggc acctttgaat tgcaaggccc cagcagccaa ggcgatgggt 25320 cttctcctgg gcaaagttta aaactgaccc cgggactgtg gacctccgcc tacttgcgca 25380 agtttgctcc ggaagattac cacccctatg aaatcaagtt ctatgaggac caatcacagc 25440 ctccaaaggc cgaactttcg gcctgcgtca tcacccaggg ggcaattctg gcccaattgc 25500 aagccatcca aaaatcccgc caagaatttc tactgaaaaa gggtaagggg gtctaccttg 25560 acccccagac cggcgaggaa ctcaacacaa ggttccctca ggatgtccca acgacgagaa 25620 aacaagaagt tgaaggtgca gccgccgccc ccagaagata tggaggaaga ttgggacagt 25680 caggcagagg aggcggagga ggacagtctg gaggacagtc tggaggaaga cagtttggag 25740 gaggaaaacg aggaggcaga ggaggtggaa gaagtaaccg ccgacaaaca gttatcctcg 25800 gctgcggaga caagcaacag cgctaccatc tccgctccga gtcgaggaac ccggcggcgt 25860 cccagcagta gatgggacga gaccggacgc ttcccgaacc caaccagcgc ttccaagacc 25920 ggtaagaagg atcggcaggg atacaagtcc tggcgggggc ataagaatgc catcatctcc 25980 tgcttgcatg agtgcggggg caacatatcc ttcacgcggc gctacttgct attccaccat 26040 ggggtgaact ttccgcgcaa tgttttgcat tactaccgtc acctccacag cccctactat 26100 agccagcaaa tcccggcagt ctcgacagat aaagacagcg gcggcgacct ccaacagaaa 26160 accagcagcg gcagttagaa aatacacaac aagtgcagca acaggaggat taaagattac 26220 agccaacgag ccagcgcaaa cccgagagtt aagaaatcgg atctttccaa ccctgtatgc 26280 catcttccag cagagtcggg gtcaagagca ggaactgaaa ataaaaaacc gatctctgcg 26340 ttcgctcacc agaagttgtt tgtatcacaa gagcgaagat caacttcagc gcactctcga 26400 ggacgccgag gctctcttca acaagtactg cgcgctgact cttaaagagt aggcagcgac 26460 cgcgcttatt caaaaaaggc gggaattaca tcatcctcga catgagtaaa gaaattccca 26520 cgccttacat gtggagttat caaccccaaa tgggattggc ggcaggcgcc tcccaggact 26580 actccacccg catgaattgg ctcagcgccg ggccttctat gatttctcga gttaatgata 26640 tacgcgccta ccgaaaccaa atacttttgg aacagtcagc tcttaccacc acgccccgcc 26700 aacaccttaa tcccagaaat tggcccgccg ccctagtgta ccaggaaagt cccgctccca 26760 ccactgtatt acttcctcga gacgcccagg ccgaagtcca aatgactaat gcaggtgcgc 26820 agttagctgg cggctccacc ctatgtcgtc acaggcctcg gcataatata aaacgcctga 26880 tgatcagagg ccgaggtatc cagctcaacg acgagtcggt gagctctccg cttggtctac 26940 gaccagacgg aatctttcag attgccggct gcgggagatc ttccttcacc cctcgtcagg 27000 ctgttctgac tttggaaagt tcgtcttcgc aaccccgctc gggcggaatc gggaccgttc 27060 aatttgtgga ggagtttact ccctctgtct acttcaaccc cttctccgga tctcctgggc 27120 attacccgga cgagttcata ccgaacttcg acgcgattag cgagtcagtg gacggctacg 27180 attgatgtct ggtgacgcgg ctgagctatc tcggctgcga catctagacc actgccgccg 27240 ctttcgctgc tttgcccggg aactcattga gttcatctac ttcgaactcc ccaaggatca 27300 ccctcaaggt ccggcccacg gagtgcggat ttctatcgaa ggcaaaatag actctcgcct 27360 gcaacgaatt ttctcccagc ggcccgtgct gatcgagcga gaccagggaa acaccacggt 27420 ttccatctac tgcatttgta atcaccccgg attgcatgaa agcctttgct gtcttatgtg 27480 tactgagttt aataaaaact gaattaagac tctcctacgg actgccgctt cttcaacccg 27540 gattttacaa ccagaagaac gaaacttttc ctgtcgtcca ggactctgtt aacttcacct 27600 ttcctactca caaactagaa gctcaacgac tacaccgctt ttccagaagc attttcccta 27660 ctaatactac tttcaaaacc ggaggtgagc tccaaggtct tcctacagaa aacccttggg 27720 tggaagcggg ccttgtagtg ctaggaattc ttgcgggtgg gcttgtgatt attctttgct 27780 acctatacac accttgcttc actttcttag tggtgttgtg gtattggttt aaaaaatggg 27840 gcccatacta gtcttgcttg ttttactttc gcttttggaa ccgggttctg ccaattacga 27900 tccatgtcta gacttcgacc cagaaaactg cacacttact tttgcacccg acacaagccg 27960 catctgtgga gttcatcgcc tctcttacga acttggcccc caacgacaaa aatttacctg 28020 catggtggga atcaacccca tagttatcac ccagcaaagt ggagatacta agggttgcat 28080 tcactgctcc tgcgattcca tcgagtgcac ctacaccctg ctgaagaccc tatgcggcct 28140 aagagacctg ctaccaatga attaaaaaat gattaataaa aaatcactta cttgaaatca 28200 gcaataaggt ctctgttgaa attttctccc agcagcacct cacttccctc ttcccaactc 28260 tggtattcta aaccccgttc agcggcatac tttctccata ctttaaaggg gatgtcaaat 28320 tttagctcct ctcctgtacc cacaatcttc atgtctttct tcccagatga ccaagagagt 28380 ccggctcagt gactccttca accctgtcta cccctatgaa gatgaaagca cctcccaaca 28440 cccctttata aacccagggt ttatttcccc aaatggcttc acacaaagcc caaacggagt 28500 tcttacttta aaatgtttaa ccccactaac aaccacaggc ggatctctac agctaaaagt 28560 gggaggggga cttacagtgg atgacaccaa cggttttttg aaagaaaaca taagtgccac 28620 cacaccactc gttaagactg gtcactctat aggtttacca ctaggagccg gattgggaac 28680 gaatgaaaat aaactttgta tcaaattagg acaaggactt acattcaatt caaacaacat 28740 ttgcattgat gacaatatta acaccttatg gacaggagtc aaccccaccg aagccaactg 28800 tcaaatcatg aactccagtg aatctaatga ttgcaaatta attctaacac tagttaaaac 28860 tggagcacta gtcactgcat ttgtttatgt tataggagta tctaacaatt ttaatatgct 28920 aactacacac agaaatataa attttactgc agagctgttt ttcgattcta ctggtaattt 28980 actaactaga ctctcatccc tcaaaactcc acttaatcat aaatcaggac aaaacatggc 29040 tactggtgcc attactaatg ctaaaggttt catgcccagc acgactgcct atcctttcaa 29100 tgataattct agagaaaaag aaaactacat ttacggaact tgttactaca cagctagtga 29160 tcgcactgct tttcccattg acatatctgt catgcttaac cgaagagcaa taaatgacga 29220 gacatcatat tgtattcgta taacttggtc ctggaacaca ggagatgccc cagaggtgca 29280 aacctctgct acaaccctag tcacctcccc atttaccttt tactacatca gagaagacga 29340 ctgacaaata aagtttgcga tcgccaggcc caccatggga tggagctgta tcatcctctt 29400 cttggtagca acagctacag gtgtccactc ccaggtgcag ctgcagcagt ctggggctga 29460 actggcaaga cctggggcct cagtgaagat gtcctgcaag gcttctggct acacctttac 29520 taggtacacg atgcactggg taaaacagag gcctggacag ggtctggaat ggattggata 29580 cattaatcct agccgtggtt atactaatta caatcagaag ttcaaggaca aggccacatt 29640 gactacagac aaatcctcca gcacagccta catgcaactg agcagcctga catctgagga 29700 ctctgcagtc tattactgtg caagatatta tgatgatcat tactgccttg actactgggg 29760 ccaaggcacc actctcacag tctcctcagg tggcggtggc tcgggcggtg gtggatctgg 29820 tggcggcgga tctgatatcg tgctcactca gtctccagca atcatgtctg catctccagg 29880 ggagaaggtc accatgacct gcagtgccag ctcaagtgta agttacatga actggtacca 29940 gcagaagtca ggcacctccc ccaaaagatg gatttatgac acatccaaac tggcttctgg 30000 agtccctgct cacttcaggg gcagtgggtc tgggacctct tactctctca caatcagcgg 30060 catggaggct gaagatgctg ccacttatta ctgccagcag tggagtagta acccattcac 30120 gttcggctcg gggacaaagt tggaaataaa ccggggatcc gaacaaaaac tcatctcaga 30180 agaggatctg aatgctgtgg gccaggacac gcaggaggtc atcgtggtgc cacactcctt 30240 gccctttaag gtggtggtga tctcagccat cctggccctg gtggtgctca ccatcatctc 30300 ccttatcatc ctcatcatgc tttggcagaa gaagccacgt taagctagct tgactgactg 30360 agatacagcg taccttcagc tcacagacat gataagatac attgatgagt ttggacaaac 30420 cacaactaga atgcagtgaa aaaaatgctt tatttgtgaa atttgtgatg ctattgcttt 30480 atttgtaacc attataagct gcaataaaca agttaacaac aacaattgca ttcattttat 30540 gtttcaggtt cagggggagg tgtgggaggt tttttaaagc aagtaaaacc tctacaaatg 30600 tggtagtcgt cagctatcct gcaggaactt gtttatttga aaatcaattc acaaaatccg 30660 agtagttatt ttgcctcccc cttcccattt aacagaatac accaatctct ccccacgcac 30720 agctttaaac atttggatac cattagatat agacatggtt ttagattcca cattccaaac 30780 agtttcagag cgagccaatc tggggtcagt gatagataaa aatccatcgg gatagtcttt 30840 taaagcgctt tcacagtcca actgctgcgg atgcgactcc ggagtctgga tcacggtcat 30900 ctggaagaag aacgatggga atcataatcc gaaaacggta tcggacgatt gtgtctcatc 30960 aaacccacaa gcagccgctg tctgcgtcgc tccgtgcgac tgctgtttat gggatcaggg 31020 tccacagtgt cctgaagcat gattttaata gcccttaaca tcaactttct ggtgcgatgc 31080 gcgcagcaac gcattctgat ttcactcaaa tctttgcagt aggtacaaca cattattaca 31140 atattgttta ataaaccata attaaaagcg ctccagccaa aactcatatc tgatataatc 31200 gcccctgcat gaccatcata ccaaagttta atataaatta aatgacgttc cctcaaaaac 31260 acactaccca catacatgat ctcttttggc atgtgcatat taacaatctg tctgtaccat 31320 ggacaacgtt ggttaatcat gcaacccaat ataaccttcc ggaaccacac tgccaacacc 31380 gctcccccag ccatgcattg aagtgaaccc tgctgattac aatgacaatg aagaacccaa 31440 ttctctcgac cgtgaatcac ttgagaatga aaaatatcta tagtggcaca acatagacat 31500 aaatgcatgc atcttctcat aatttttaac tcctcaggat ttagaaacat atcccaggga 31560 ataggaagct cttgcagaac agtaaagctg gcagaacaag gaagaccacg aacacaactt 31620 acactatgca tagtcatagt atcacaatct ggcaacagcg ggtggtcttc agtcatagaa 31680 gctcgggttt cattttcctc acaacgtggt aactgggctc tggtgtaagg gtgatgtctg 31740 gcgcatgatg tcgagcgtgc gcgcaacctt gtcataatgg agttgcttcc tgacattctc 31800 gtattttgta tagcaaaacg cggccctggc agaacacact cttcttcgcc ttctatcctg 31860 ccgcttagcg tgttccgtgt gatagttcaa gtacaaccac actcttaagt tggtcaaaag 31920 aatgctggct tcagttgtaa tcaaaactcc atcgcatcta atcgttctga ggaaatcatc 31980 caagcaatgc aactggattg tgtttcaagc aggagaggag agggaagaga cggaagaacc 32040 atgttaattt ttattccaaa cgatctcgca gtacttcaaa ttgtagatcg cgcagatggc 32 100 atctctcgcc cccactgtgt tggtgaaaaa gcacagctag atcaaaagaa atgcgatttt 32160 caaggtgctc aacggtggct tccagcaaag cctccacgcg cacatccaag aacaaaagaa 32220 taccaaaaga aggagcattt tctaactcct caatcatcat attacattcc tgcaccattc 32280 ccagataatt ttcagctttc cagccttgaa ttattcgtgt cagttcttgt ggtaaatcca 32340 atccacacat tacaaacagg tcccggaggg cgccctccac caccattctt aaacacaccc 32400 tcataatgac aaaatatctt gctcctgtgt cacctgtagc gaattgagaa tggcaacatc 32460 aattgacatg cccttggctc taagttcttc tttaagttct agttgtaaaa actctctcat 32520 attatcacca aactgcttag ccagaagccc cccgggaaca agagcagggg acgctacagt 32580 gcagtacaag cgcagacctc cccaattggc tccagcaaaa acaagattgg aataagcata 32640 ttgggaaccg ccagtaatat catcgaagtt gctggaaata taatcaggca gagtttcttg 32700 taaaaattga ataaaagaaa aatttgccaa aaaaacattc aaaacctctg ggatgcaaat 32760 gcaataggtt accgcgctgc gctccaacat tgttagtttt gaattagtct gcaaaaataa 32820 aaaaaaaaac aagcgtcata tcatagtagc ctgacgaaca gatggataaa tcagtctttc 32880 catcacaaga caagccacag ggtctccagc tcgaccctcg taaaacctgt catcatgatt 32940 aaacaacagc accgaaagtt cctcgcggtg accagcatga ataattcttg atgaagcata 33000 caatccagac atgttagcat cagttaacga gaaaaaacag ccaacatagc ctttgggtat 33060 aattatgctt aatcgtaagt atagcaaagc cacccctcgc ggatacaaag taaaaggcac 33 120 aggagaataa aaaatataat tatttctctg ctgctgttca ggcaacgtcg cccccggtcc 33180 ctctaaatac acatacaaag cctcatcagc catggcttac cagacaaagt acagcgggca 33240 cacaaagcac aagctctaaa gtgactctcc aacctctcca caatatatat atacacaagc 33300 cctaaactga cgtaatggga gtaaagtgta aaaaatcccg ccaaacccaa cacacacccc 33360 gaaactgcgt caccagggaa aagtacagtt tcacttccgc aatcccaaca ggcgtaactt 33420 cctctttctc acggtacgtg atatcccact aacttgcaac gtcattttcc cacggtcgca 33480 ccgccccttt tagccgttaa ccccacagcc aatcaccaca cgatccacac tttttaaaat 33540 cacctcattt acatattggc accattccat ctataaggta tattatatag ataga 33595 <210> 103 <211> 33628 <212> DNA <213> Artificial Sequence <220> <223> NG-420 virus genome sequence comprising a transgene cassette encoding a membrane-anchored chimeric form of the anti-human CD3e scFv with a C-terminal V5 tag inserted in the region BY <400> 103 tctatctata taatatacct tatagatgga atggtgccaa tatgtaaatg aggtgatttt 60 aaaaagtgtg gatcgtgtgg tgattggctg tggggttaac ggctaaaagg ggcggtgcga 120 ccgtgggaaa atgacgtttt gtgggggtgg agtttttttg caagttgtcg cgggaaatgt 180 gacgcataaa aaggcttttt tctcacggaa ctacttagtt ttcccacggt atttaacagg 240 aaatgaggta gttttgaccg gatgcaagtg aaaattgttg attttcgcgc gaaaactgaa 300 tgaggaagtg tttttctgaa taatgtggta tttatggcag ggtggagtat ttgttcaggg 360 ccaggtagac tttgacccat tacgtggagg tttcgattac cgtgtttttt acctgaattt 420 ccgcgtaccg tgtcaaagtc ttctgttttt acgtaggtgt cagctgatcg ctagggtatt 480 tatacctcag ggtttgtgtc aagaggccac tcttgagtgc cagcgagaag agttttctcc 540 tctgcgccgg cagtttaata ataaaaaaat gagagatttg cgatttctgc ctcaggaaat 600 aatctctgct gagactggaa atgaaatatt ggagcttgtg gtgcacgccc tgatgggaga 660 cgatccggag ccacctgtgc agctttttga gcctcctacg cttcaggaac tgtatgattt 720 agaggtagag ggatcggagg attctaatga ggaagctgta aatggctttt ttaccgattc 780 tatgctttta gctgctaatg aagggttaga attagatccg cctttggaca cttttgatac 840 tccaggggta attgtggaaa gcggtacagg tgtaagaaaa ttacctgatt tgagttccgt 900 ggactgtgat ttgcactgct atgaagacgg gtttcctccg agtgatgagg aggaccatga 960 aaaggagcag tccatgcaga ctgcagcggg tgagggagtg aaggctgcca atgttggttt 1020 tcagttggat tgcccggagc ttcctggaca tggctgtaag tcttgtgaat ttcacaggaa 1080 aaatactgga gtaaaggaac tgttatgttc gctttgttat atgagaacgc actgccactt 1140 tatttacagt aagtgtgttt aagttaaaat ttaaaggaat atgctgtttt tcacatgtat 1200 attgagtgtg agttttgtgc ttcttattat aggtcctgtg tctgatgctg atgaatcacc 1260 atctcctgat tctactacct cacctcctga gattcaagca cctgttcctg tggacgtgcg 1320 caagcccatt cctgtgaagc ttaagcctgg gaaacgtcca gcagtggaaa aacttgagga 1380 cttgttacag ggtggggacg gacctttgga cttgagtaca cggaaacgtc caagacaata 1440 agtgttccat atccgtgttt acttaaggtg acgtcaatat ttgtgtgaca gtgcaatgta 1500 ataaaaatat gttaactgtt cactggtttt tattgctttt tgggcgggga ctcaggtata 1560 taagtagaag cagacctgtg tggttagctc ataggagctg gctttcatcc atggaggttt 1620 gggccatttt ggaagacctt aggaagacta ggcaactgtt agagaacgct tcggacggag 1680 tctccggttt ttggagattc tggttcgcta gtgaattagc tagggtagtt tttaggataa 1740 aacaggacta taaacaagaa tttgaaaagt tgttggtaga ttgcccagga ctttttgaag 1800 ctcttaattt gggccatcag gttcacttta aagaaaaagt tttatcagtt ttagactttt 1860 caaccccagg tagaactgct gctgctgtgg cttttcttac ttttatatta gataaatgga 1920 tcccgcagac tcatttcagc aggggatacg ttttggattt catagccaca gcattgtgga 1980 gaacatggaa ggttcgcaag atgaggacaa tcttaggtta ctggccagtg cagcctttgg 2040 gtgtagcggg aatcctgagg catccaccgg tcatgccagc ggttctggag gaggaacagc 2100 aagaggacaa cccgagagcc ggcctggacc ctccagtgga ggaggcggag tagctgactt 2160 gtctcctgaa ctgcaacggg tgcttactgg atctacgtcc actggacggg ataggggcgt 2220 taagagggag agggcatcta gtggtactga tgctagatct gagttggctt taagtttaat 2280 gagtcgcaga cgtcctgaaa ccatttggtg gcatgaggtt cagaaagagg gaagggatga 2340 agtttctgta ttgcaggaga aatattcact ggaacaggtg aaaacatgtt ggttggagcc 2400 tgaggatgat tgggaggtgg ccattaaaaa ttatgccaag atagctttga ggcctgataa 2460 acagtataag attactagac ggattaatat ccggaatgct tgttacatat ctggaaatgg 2520 ggctgaggtg gtaatagata ctcaagacaa ggcagttatt agatgctgca tgatggatat 2580 gtggcctggg gtagtcggta tggaagcagt aacttttgta aatgttaagt ttaggggaga 2640 tggttataat ggaatagtgt ttatggccaa taccaaactt atattgcatg gttgtagctt 2700 ttttggtttc aacaatacct gtgtagatgc ctggggacag gttagtgtac ggggatgtag 2760 tttctatgcg tgttggattg ccacagctgg cagaaccaag agtcaattgt ctctgaagaa 2820 atgcatattt caaagatgta acctgggcat tctgaatgaa ggcgaagcaa gggtccgcca 2880 ctgcgcttct acagatactg gatgttttat tttgattaag ggaaatgcca gcgtaaagca 2940 taacatgatt tgcggtgctt ccgatgagag gccttatcaa atgctcactt gtgctggtgg 3000 gcattgtaat atgctggcta ctgtgcatat tgtttcccat caacgcaaaa aatggcctgt 3060 ttttgatcac aatgtgatga cgaagtgtac catgcatgca ggtgggcgta gaggaatgtt 3120 tatgccttac cagtgtaaca tgaatcatgt gaaagtgttg ttggaaccag atgccttttc 3180 cagaatgagc ctaacaggaa tttttgacat gaacatgcaa atctggaaga tcctgaggta 3240 tgatgatacg agatcgaggg tacgcgcatg cgaatgcgga ggcaagcatg ccaggttcca 3300 gccggtgtgt gtagatgtga ctgaagatct cagaccggat catttggtta ttgcccgcac 3360 tggagcagag ttcggatcca gtggagaaga aactgactaa ggtgagtatt gggaaaactt 3420 tggggtggga ttttcagatg gacagattga gtaaaaattt gttttttctg tcttgcagct 3480 gtcatgagtg gaaacgcttc ttttaagggg ggagtcttca gcccttatct gacagggcgt 3540 ctcccatcct gggcaggagt tcgtcagaat gttatgggat ctactgtgga tggaagaccc 3600 gtccaacccg ccaattcttc aacgctgacc tatgctactt taagttcttc acctttggac 3660 gcagctgcag ctgccgccgc cgcttctgtt gccgctaaca ctgtgcttgg aatgggttac 3720 tatggaagca tcatggctaa ttccacttcc tctaataacc cttctaccct gactcaggac 3780 aagttacttg tccttttggc ccagctggag gctttgaccc aacgtctggg tgaactttct 3840 cagcaggtgg tcgagttgcg agtacaaact gagtctgctg tcggcacggc aaagtctaaa 3900 taaaaaaatc ccagaatcaa tgaataaata aacaagcttg ttgttgattt aaaatcaagt 3960 gtttttattt catttttcgc gcacggtatg ccctagacca ccgatctcta tcattgagaa 4020 ctcggtggat tttttccagg atcctataga ggtgggattg aatgtttaga tacatgggca 4080 ttaggccgtc tttggggtgg agatagctcc attgaaggga ttcatgctcc ggggtagtgt 4140 tgtaaatcac ccagtcataa caaggtcgca gtgcatggtg ttgcacaata tcttttagaa 4200 gtaggctgat tgccacagat aagcccttgg tgtaggtgtt tacaaaccgg ttgagctggg 4260 atgggtgcat tcggggtgaa attatgtgca ttttggattg gatttttaag ttggcaatat 4320 tgccgccaag atcccgtctt gggttcatgt tatgaaggac caccaagacg gtgtatccgg 4380 tacatttagg aaatttatcg tgcagcttgg atggaaaagc gtggaaaaat ttggagacac 4440 ccttgtgtcc tccaagattt tccatgcact catccatgat aatagcaatg gggccgtggg 4500 cagcggcgcg ggcaaacacg ttccgtgggt ctgacacatc atagttatgt tcctgagtta 4560 aatcatcata agccatttta atgaatttgg ggcggagagt accagattgg ggtatgaatg 4620 ttccttcggg ccccggagca tagttcccct cacagatttg catttcccaa gctttcagtt 4680 ccgagggtgg aatcatgtcc acctgggggg ctatgaaaaa caccgtttct ggggcggggg 4740 tgattaattg tgatgatagc aaatttctga gcaattgaga tttgccacat ccggtggggc 4800 cataaatgat tccgattacg ggttgcaggt ggtagtttag ggaacggcaa ctgccgtctt 4860 ctcgaagcaa gggggccacc tcgttcatca tttcccttac atgcatattt tcccgcacca 4920 aatccattag gaggcgctct cctcctagtg atagaagttc ttgtagtgag gaaaagtttt 4980 tcagcggttt cagaccgtca gccatgggca ttttggagag agtttgctgc aaaagttcta 5040 gtctgttcca cagttcagtg atgtgttcta tggcatctcg atccagcaga cctcctcgtt 5100 tcgcgggttt ggacggctcc tggaataggg tatgagacga tgggcgtcca gcgctgccag 5160 ggttcggtcc ttccagggtc tcagtgttcg agtcagggtt gtttccgtca cagtgaaggg 5220 gtgtgcgcct gcttgggcgc ttgccagggt gcgcttcaga ctcatcctgc tggtcgaaaa 5280 cttctgtcgc ttggcgccct gtatgtcggc caagtagcag tttaccatga gttcgtagtt 5340 gagcgcctcg gctgcgtggc ctttggcgcg gagcttacct ttggaagttt tcttgcatac 5400 cgggcagtat aggcatttca gcgcatacaa cttgggcgca aggaaaacgg attctgggga 5460 gtatgcatct gcgccgcagg aggcgcaaac agtttcacat tccaccagcc aggttaaatc 5520 cggttcattg gggtcaaaaa caagttttcc gccatatttt ttgatgcgtt tcttaccttt 5580 ggtctccatg agttcgtgtc ctcgttgagt gacaaacagg ctgtccgtgt ccccgtagac 5640 tgattttaca ggcctcttct ccagtggagt gcctcggtct tcttcgtaca ggaactctga 5700 ccactctgat acaaaggcgc gcgtccaggc cagcacaaag gaggctatgt gggaggggta 5760 gcgatcgttg tcaaccaggg ggtccacctt ttccaaagta tgcaaacaca tgtcaccctc 5820 ttcaacatcc aggaatgtga ttggcttgta ggtgtatttc acgtgacctg gggtccccgc 5880 tgggggggta taaaaggggg cggttctttg ctcttcctca ctgtcttccg gatcgctgtc 5940 caggaacgtc agctgttggg gtaggtattc cctctcgaag gcgggcatga cctctgcact 6000 caggttgtca gtttctaaga acgaggagga tttgatattg acagtgccgg ttgagatgcc 6060 tttcatgagg ttttcgtcca tctggtcaga aaacacaatt tttttattgt caagtttggt 6120 ggcaaatgat ccatacaggg cgttggataa aagtttggca atggatcgca tggtttggtt 6180 cttttccttg tccgcgcgct ctttggcggc gatgttgagt tggacatact cgcgtgccag 6240 gcacttccat tcggggaaga tagttgttaa ttcatctggc acgattctca cttgccaccc 6300 tcgattatgc aaggtaatta aatccacact ggtggccacc tcgcctcgaa ggggttcatt 6360 ggtccaacag agcctacctc ctttcctaga acagaaaggg ggaagtgggt ctagcataag 6420 ttcatcggga gggtctgcat ccatggtaaa gattcccgga agtaaatcct tatcaaaata 6480 gctgatggga gtggggtcat ctaaggccat ttgccattct cgagctgcca gtgcgcgctc 6540 atatgggtta aggggactgc cccatggcat gggatgggtg agtgcagagg catacatgcc 6600 acagatgtca tagacgtaga tgggatcctc aaagatgcct atgtaggttg gatagcatcg 6660 cccccctctg atacttgctc gcacatagtc atatagttca tgtgatggcg ctagcagccc 6720 cggacccaag ttggtgcgat tgggtttttc tgttctgtag acgatctggc gaaagatggc 6780 gtgagaattg gaagagatgg tgggtctttg aaaaatgttg aaatgggcat gaggtagacc 6840 tacagagtct ctgacaaagt gggcataaga ttcttgaagc ttggttacca gttcggcggt 6900 gacaagtacg tctagggcgc agtagtcaag tgtttcttga atgatgtcat aacctggttg 6960 gtttttcttt tcccacagtt cgcggttgag aaggtattct tcgcgatcct tccagtactc 7020 ttctagcgga aacccgtctt tgtctgcacg gtaagatcct agcatgtaga actgattaac 7080 tgccttgtaa gggcagcagc ccttctctac gggtagagag tatgcttgag cagcttttcg 7140 tagcgaagcg tgagtaaggg caaaggtgtc tctgaccatg actttgagga attggtattt 7200 gaagtcgatg tcgtcacagg ctccctgttc ccagagttgg aagtctaccc gtttcttgta 7260 ggcggggttg ggcaaagcga aagtaacatc attgaagaga atcttgccgg ccctgggcat 7320 gaaattgcga gtgatgcgaa aaggctgtgg tacttccgct cggttattga taacctgggc 7380 agctaggacg atctcgtcga aaccgttgat gttgtgtcct acgatgtata attctatgaa 7440 acgcggcgtg cctctgacgt gaggtagctt actgagctca tcaaaggtta ggtctgtggg 7500 gtcagataag gcgtagtgtt cgagagccca ttcgtgcagg tgaggattcg ctttaaggaa 7560 ggaggaccag aggtccactg ccagtgctgt ttgtaactgg tcccggtact gacgaaaatg 7620 ccgtccgact gccatttttt ctggggtgac gcaatagaag gtttgggggt cctgccgcca 7680 gcgatcccac ttgagtttta tggcgaggtc ataggcgatg ttgacgagcc gctggtctcc 7740 agagagtttc atgaccagca tgaaggggat tagctgcttg ccaaaggacc ccatccaggt 7800 gtaggtttcc acatcgtagg tgagaaagag cctttctgtg cgaggatgag agccaatcgg 7860 gaagaactgg atctcctgcc accagttgga ggaatggctg ttgatgtgat ggaagtagaa 7920 ctccctgcga cgcgccgagc attcatgctt gtgcttgtac agacggccgc agtagtcgca 7980 gcgttgcacg ggttgtatct cgtgaatgag ttgtacctgg cttcccttga cgagaaattt 8040 cagtgggaag ccgaggcctg gcgattgtat ctcgtgcttt actatgttgt ctgcatcggc 8100 ctgttcatct tctgtctcga tggtggtcat gctgacgagc cctcgcggga ggcaagtcca 8160 gacctcggcg cggcaggggc ggagctcgag gacgagagcg cgcaggctgg agctgtccag 8220 ggtcctgaga cgctgcggac tcaggttagt aggcagtgtc aggagattaa cttgcatgat 8280 cttttggagg gcgtgcggga ggttcagata gtacttgatc tcaacgggtc cgttggtgga 8340 gatgtcgatg gcttgcaggg ttccgtgtcc cttgggcgct accaccgtgc ccttgttttt 8400 cattttggac ggcggtggct ctgttgcttc ttgcatgttt agaagcggtg tcgagggcgc 8460 gcaccgggcg gcaggggcgg ctcgggaccc ggcggcatgg ctggcagtgg tacgtcggcg 8520 ccgcgcgcgg gtaggttctg gtactgcgcc ctgagaagac tcgcatgcgc gacgacgcgg 8580 cggttgacat cctggatctg acgcctctgg gtgaaagcta ccggccccgt gagcttgaac 8640 ctgaaagaga gttcaacaga atcaatctcg gtatcgttga cggcggcttg cctaaggatt 8700 tcttgcacgt caccagagtt gtcctggtag gcgatctccg ccatgaactg ctcgatctct 8760 tcctcttgaa gatctccgcg gcccgctctc tcgacggtgg ccgcgaggtc gttggagatg 8820 cgcccaatga gttgagagaa tgcattcatg cccgcctcgt tccagacgcg gctgtagacc 8880 acggccccca cgggatctct cgcgcgcatg accacctggg cgaggttgag ctccacgtgg 8940 cgggtgaaga ccgcatagtt gcataggcgc tggaaaaggt agttgagtgt ggtggcgatg 9000 tgctcggtga cgaagaaata catgatccat cgtctcagcg gcatctcgct gacatcgccc 9060 agagcttcca agcgctccat ggcctcgtag aagtccacgg caaaattaaa aaactgggag 9120 tttcgcgcgg acacggtcaa ctcctcttcc agaagacgga taagttcggc gatggtggtg 9180 cgcacctcgc gctcgaaagc ccctgggatt tcttcctcaa tctcttcttc ttccactaac 9240 atctcttcct cttcaggtgg ggctgcagga ggagggggaa cgcggcgacg ccggcggcgc 9300 acgggcagac ggtcgatgaa tctttcaatg acctctccgc ggcggcggcg catggtttca 9360 gtgacggcgc ggccgttctc gcgcggtcgc agagtaaaaa caccgccgcg catctcctta 9420 aagtggtgac tgggaggttc tccgtttggg agggagaggg cgctgattat acattttatt 9480 aattggcccg tagggactgc acgcagagat ctgatcgtgt caagatccac gggatctgaa 9540 aacctttcga cgaaagcgtc taaccagtca cagtcacaag gtaggctgag tacggcttct 9600 tgtgggcggg ggtggttatg tgttcggtct gggtcttctg tttcttcttc atctcgggaa 9660 ggtgagacga tgctgctggt gatgaaatta aagtaggcag ttctaagacg gcggatggtg 9720 gcgaggagca ccaggtcttt gggtccggct tgctggatac gcaggcgatt ggccattccc 9780 caagcattat cctgacatct agcaagatct ttgtagtagt cttgcatgag ccgttctacg 9840 ggcacttctt cctcacccgt tctgccatgc atacgtgtga gtccaaatcc gcgcattggt 9900 tgtaccagtg ccaagtcagc tacgactctt tcggcgagga tggcttgctg tacttgggta 9960 agggtggctt gaaagtcatc aaaatccaca aagcggtggt aagctcctgt attaatggtg 10020 taagcacagt tggccatgac tgaccagtta actgtctggt gaccagggcg cacgagctcg 10080 gtgtatttaa ggcgcgaata ggcgcgggtg tcaaagatgt aatcgttgca ggtgcgcacc 10140 agatactggt accctataag aaaatgcggc ggtggttggc ggtagagagg ccatcgttct 10200 gtagctggag cgccaggggc gaggtcttcc aacataaggc ggtgatagcc gtagatgtac 10260 ctggacatcc aggtgattcc tgcggcggta gtagaagccc gaggaaactc gcgtacgcgg 10320 ttccaaatgt tgcgtagcgg catgaagtag ttcattgtag gcacggtttg accagtgagg 10380 cgcgcgcagt cattgatgct ctatagacac ggagaaaatg aaagcgttca gcgactcgac 10440 tccgtagcct ggaggaacgt gaacgggttg ggtcgcggtg taccccggtt cgagacttgt 10500 actcgagccg gccggagccg cggctaacgt ggtattggca ctcccgtctc gacccagcct 10560 acaaaaatcc aggatacgga atcgagtcgt tttgctggtt tccgaatggc agggaagtga 10620 gtcctatttt ttttttttgc cgctcagatg catcccgtgc tgcgacagat gcgcccccaa 10680 caacagcccc cctcgcagca gcagcagcag caatcacaaa aggctgtccc tgcaactact 10740 gcaactgccg ccgtgagcgg tgcgggacag cccgcctatg atctggactt ggaagagggc 10800 gaaggactgg cacgtctagg tgcgccttca cccgagcggc atccgcgagt tcaactgaaa 10860 aaagattctc gcgaggcgta tgtgccccaa cagaacctat ttagagacag aagcggcgag 10920 gagccggagg agatgcgagc ttcccgcttt aacgcgggtc gtgagctgcg tcacggtttg 10980 gaccgaagac gagtgttgcg ggacgaggat ttcgaagttg atgaaatgac agggatcagt 11040 cctgccaggg cacacgtggc tgcagccaac cttgtatcgg cttacgagca gacagtaaag 11 100 gaagagcgta acttccaaaa gtcttttaat aatcatgtgc gaaccctgat tgcccgcgaa 11160 gaagttaccc ttggtttgat gcatttgtgg gatttgatgg aagctatcat tcagaaccct 11220 actagcaaac ctctgaccgc ccagctgttt ctggtggtgc aacacagcag agacaatgag 11280 gctttcagag aggcgctgct gaacatcacc gaacccgagg ggagatggtt gtatgatctt 11340 atcaacattc tacagagtat catagtgcag gagcggagcc tgggcctggc cgagaaggtg 11400 gctgccatca attactcggt tttgagcttg ggaaaatatt acgctcgcaa aatctacaag 11460 actccatacg ttcccataga caaggaggtg aagatagatg ggttctacat gcgcatgacg 11520 ctcaaggtct tgaccctgag cgatgatctt ggggtgtatc gcaatgacag aatgcatcgc 11580 gcggttagcg ccagcaggag gcgcgagtta agcgacaggg aactgatgca cagtttgcaa 11640 agagctctga ctggagctgg aaccgagggt gagaattact tcgacatggg agctgacttg 11700 cagtggcagc ctagtcgcag ggctctgagc gccgcgacgg caggatgtga gcttccttac 11760 atagaagagg cggatgaagg cgaggaggaa gagggcgagt acttggaaga ctgatggcac 11820 aacccgtgtt ttttgctaga tggaacagca agcaccggat cccgcaatgc gggcggcgct 11880 gcagagccag ccgtccggca ttaactcctc ggacgattgg acccaggcca tgcaacgtat 11940 catggcgttg acgactcgca accccgaagc ctttagacag caaccccagg ccaaccgtct 12000 atcggccatc atggaagctg tagtgccttc ccgctctaat cccactcatg agaaggtcct 12060 ggccatcgtg aacgcgttgg tggagaacaa agctattcgt ccagatgagg ccggactggt 12120 atacaacgct ctcttagaac gcgtggctcg ctacaacagt agcaatgtgc aaaccaattt 12180 ggaccgtatg ataacagatg tacgcgaagc cgtgtctcag cgcgaaaggt tccagcgtga 12240 tgccaacctg ggttcgctgg tggcgttaaa tgctttcttg agtactcagc ctgctaatgt 12300 gccgcgtggt caacaggatt atactaactt tttaagtgct ttgagactga tggtatcaga 12360 agtacctcag agcgaagtgt atcagtccgg tcctgattac ttctttcaga ctagcagaca 12420 gggcttgcag acggtaaatc tgagccaagc ttttaaaaac cttaaaggtt tgtggggagt 12480 gcatgccccg gtaggagaaa gagcaaccgt gtctagcttg ttaactccga actcccgcct 12540 attattactg ttggtagctc ctttcaccga cagcggtagc atcgaccgta attcctattt 12600 gggttaccta ctaaacctgt atcgcgaagc catagggcaa agtcaggtgg acgagcagac 12660 ctatcaagaa attacccaag tcagtcgcgc tttgggacag gaagacactg gcagtttgga 12720 agccactctg aacttcttgc ttaccaatcg gtctcaaaag atccctcctc aatatgctct 12780 tactgcggag gaggagagga tccttagata tgtgcagcag agcgtgggat tgtttctgat 12840 gcaagagggg gcaactccga ctgcagcact ggacatgaca gcgcgaaata tggagcccag 12900 catgtatgcc agtaaccgac ctttcattaa caaactgctg gactacttgc acagagctgc 12960 cgctatgaac tctgattatt tcaccaatgc catcttaaac ccgcactggc tgcccccacc 13020 tggtttctac acgggcgaat atgacatgcc cgaccctaat gacggatttc tgtgggacga 13080 cgtggacagc gatgtttttt cacctctttc tgatcatcgc acgtggaaaa aggaaggcgg 13140 cgatagaatg cattcttctg catcgctgtc cggggtcatg ggtgctaccg cggctgagcc 13200 cgagtctgca agtccttttc ctagtctacc cttttctcta cacagtgtac gtagcagcga 13260 agtgggtaga ataagtcgcc cgagtttaat gggcgaagag gagtatctaa acgattcctt 13320 gctcagaccg gcaagagaaa aaaatttccc aaacaatgga atagaaagtt tggtggataa 13380 aatgagtaga tggaagactt atgctcagga tcacagagac gagcctggga tcatggggat 13440 tacaagtaga gcgagccgta gacgccagcg ccatgacaga cagaggggtc ttgtgtggga 13500 cgatgaggat tcggccgatg atagcagcgt gctggacttg ggtgggagag gaaggggcaa 13560 cccgtttgct catttgcgcc ctcgcttggg tggtatgttg taaaaaaaaa taaaaaaaaa 13620 actcaccaag gccatggcga cgagcgtacg ttcgttcttc tttattatct gtgtctagta 13680 taatgaggcg agtcgtgcta ggcggagcgg tggtgtatcc ggagggtcct cctccttcgt 13740 acgagagcgt gatgcagcag cagcaggcga cggcggtgat gcaatcccca ctggaggctc 13800 cctttgtgcc tccgcgatac ctggcaccta cggagggcag aaacagcatt cgttattcgg 13860 aactggcacc tcagtacgat accaccaggt tgtatctggt ggacaacaag tcggcggaca 13920 ttgcttctct gaactatcag aatgaccaca gcaacttctt gaccacggtg gtgcaaaaca 13980 atgactttac ccctacggaa gccagcaccc agaccattaa ctttgatgaa cgatcgcggt 14040 ggggcggtca gctaaagacc atcatgcata ctaacatgcc aaacgtgaac gagtatatgt 14100 ttagtaacaa gttcaaagcg cgtgtgatgg tgtccagaaa acctcccgac ggtgctgcag 14160 ttggggatac ttatgatcac aagcaggata ttttgaaata tgagtggttc gagtttactt 14220 tgccagaagg caacttttca gttactatga ctattgattt gatgaacaat gccatcatag 14280 ataattactt gaaagtgggt agacagaatg gagtgcttga aagtgacatt ggtgttaagt 14340 tcgacaccag gaacttcaag ctgggatggg atcccgaaac caagttgatc atgcctggag 14400 tgtatacgta tgaagccttc catcctgaca ttgtcttact gcctggctgc ggagtggatt 14460 ttaccgagag tcgtttgagc aaccttcttg gtatcagaaa aaaacagcca tttcaagagg 14520 gttttaagat tttgtatgaa gatttagaag gtggtaatat tccggccctc ttggatgtag 14580 atgcctatga gaacagtaag aaagaacaaa aagccaaaat agaagctgct acagctgctg 14640 cagaagctaa ggcaaacata gttgccagcg actctacaag ggttgctaac gctggagagg 14700 tcagaggaga caattttgcg ccaacacctg ttccgactgc agaatcatta ttggccgatg 14760 tgtctgaagg aacggacgtg aaactcacta ttcaacctgt agaaaaagat agtaagaata 14820 gaagctataa tgtgttggaa gacaaaatca acacagccta tcgcagttgg tatctttcgt 14880 acaattatgg cgatcccgaa aaaggagtgc gttcctggac attgctcacc acctcagatg 14940 tcacctgcgg agcagagcag gtctactggt cgcttccaga catgatgaag gatcctgtca 15000 ctttccgctc cactagacaa gtcagtaact accctgtggt gggtgcagag cttatgcccg 15060 tcttctcaaa gagcttctac aacgaacaag ctgtgtactc ccagcagctc cgccagtcca 15120 cctcgcttac gcacgtcttc aaccgctttc ctgagaacca gattttaatc cgtccgccgg 15180 cgcccaccat taccaccgtc agtgaaaacg ttcctgctct cacagatcac gggaccctgc 15240 cgttgcgcag cagtatccgg ggagtccaac gtgtgaccgt tactgacgcc agacgccgca 15300 cctgtcccta cgtgtacaag gcactgggca tagtcgcacc gcgcgtcctt tcaagccgca 15360 ctttctaaaa aaaaaaaaaa tgtccattct tatctcgccc agtaataaca ccggttgggg 15420 tctgcgcgct ccaagcaaga tgtacggagg cgcacgcaaa cgttctaccc aacatcctgt 15480 ccgtgttcgc ggacattttc gcgctccatg gggcgccctc aagggccgca ctcgcgttcg 15540 aaccaccgtc gatgatgtaa tcgatcaggt ggttgccgac gcccgtaatt atactcctac 15600 tgcgcctaca tctactgtgg atgcagttat tgacagtgta gtggctgacg ctcgcaacta 15660 tgctcgacgt aagagccggc gaaggcgcat tgccagacgc caccgagcta ccactgccat 15720 gcgagccgca agagctctgc tacgaagagc tagacgcgtg gggcgaagag ccatgcttag 15780 ggcggccaga cgtgcagctt cgggcgccag cgccggcagg tcccgcaggc aagcagccgc 15840 tgtcgcagcg gcgactattg ccgacatggc ccaatcgcga agaggcaatg tatactgggt 15900 gcgtgacgct gccaccggtc aacgtgtacc cgtgcgcacc cgtccccctc gcacttagaa 15960 gatactgagc agtctccgat gttgtgtccc agcggcgagg atgtccaagc gcaaatacaa 16020 ggaagaaatg ctgcaggtta tcgcacctga agtctacggc caaccgttga aggatgaaaa 16080 aaaaccccgc aaaatcaagc gggttaaaaa ggacaaaaaa gaagaggaag atggcgatga 16140 tgggctggcg gagtttgtgc gcgagtttgc cccacggcga cgcgtgcaat ggcgtgggcg 16200 caaagttcga catgtgttga gacctggaac ttcggtggtc tttacacccg gcgagcgttc 16260 aagcgctact tttaagcgtt cctatgatga ggtgtacggg gatgatgata ttcttgagca 16320 ggcggctgac cgattaggcg agtttgctta tggcaagcgt agtagaataa cttccaagga 16380 tgagacagtg tcgataccct tggatcatgg aaatcccacc cctagtctta aaccggtcac 16440 tttgcagcaa gtgttacccg taactccgcg aacaggtgtt aaacgcgaag gtgaagattt 16500 gtatcccact atgcaactga tggtacccaa acgccagaag ttggaggacg ttttggagaa 16560 agtaaaagtg gatccagata ttcaacctga ggttaaagtg agacccatta agcaggtagc 16620 gcctggtctg ggggtacaaa ctgtagacat taagattccc actgaaagta tggaagtgca 16680 aactgaaccc gcaaagccta ctgccacctc cactgaagtg caaacggatc catggatgcc 16740 catgcctatt acaactgacg ccgccggtcc cactcgaaga tcccgacgaa agtacggtcc 16800 agcaagtctg ttgatgccca attatgttgt acacccatct attattccta ctcctggtta 16860 ccgaggcact cgctactatc gcagccgaaa cagtacctcc cgccgtcgcc gcaagacacc 16920 tgcaaatcgc agtcgtcgcc gtagacgcac aagcaaaccg actcccggcg ccctggtgcg 16980 gcaagtgtac cgcaatggta gtgcggaacc tttgacactg ccgcgtgcgc gttaccatcc 17040 gagtatcatc acttaatcaa tgttgccgct gcctccttgc agatatggcc ctcacttgtc 17100 gccttcgcgt tcccatcact ggttaccgag gaagaaactc gcgccgtaga agagggatgt 17160 tgggacgcgg aatgcgacgc tacaggcgac ggcgtgctat ccgcaagcaa ttgcggggtg 17220 gttttttacc agccttaatt ccaattatcg ctgctgcaat tggcgcgata ccaggcatag 17280 cttccgtggc ggttcaggcc tcgcaacgac attgacattg gaaaaaaacg tataaataaa 17340 aaaaaaaaaa tacaatggac tctgacactc ctggtcctgt gactatgttt tcttagagat 17400 ggaagacatc aatttttcat ccttggctcc gcgacacggc acgaagccgt acatgggcac 17460 ctggagcgac atcggcacga gccaactgaa cgggggcgcc ttcaattgga gcagtatctg 17520 gagcgggctt aaaaattttg gctcaaccat aaaaacatac gggaacaaag cttggaacag 17580 cagtacagga caggcgctta gaaataaact taaagaccag aacttccaac aaaaagtagt 17640 cgatgggata gcttccggca tcaatggagt ggtagatttg gctaaccagg ctgtgcagaa 17700 aaagataaac agtcgtttgg acccgccgcc agcaacccca ggtgaaatgc aagtggagga 17760 agaaattcct ccgccagaaa aacgaggcga caagcgtccg cgtcccgatt tggaagagac 17820 gctggtgacg cgcgtagatg aaccgccttc ttatgaggaa gcaacgaagc ttggaatgcc 17880 caccactaga ccgatagccc caatggccac cggggtgatg aaaccttctc agttgcatcg 17940 acccgtcacc ttggatttgc cccctccccc tgctgctact gctgtacccg cttctaagcc 18000 tgtcgctgcc ccgaaaccag tcgccgtagc caggtcacgt cccgggggcg ctcctcgtcc 18060 aaatgcgcac tggcaaaata ctctgaacag catcgtgggt ctaggcgtgc aaagtgtaaa 18 120 acgccgtcgc tgcttttaat taaatatgga gtagcgctta acttgcctat ctgtgtatat 18180 gtgtcattac acgccgtcac agcagcagag gaaaaaagga agaggtcgtg cgtcgacgct 18240 gagttacttt caagatggcc accccatcga tgctgcccca atgggcatac atgcacatcg 18300 ccggacagga tgcttcggag tacctgagtc cgggtctggt gcagttcgcc cgcgccacag 18360 acacctactt caatctggga aataagttta gaaatcccac cgtagcgccg acccacgatg 18420 tgaccaccga ccgtagccag cggctcatgt tgcgcttcgt gcccgttgac cgggaggaca 18480 atacatactc ttacaaagtg cggtacaccc tggccgtggg cgacaacaga gtgctggata 18540 tggccagcac gttctttgac attaggggtg tgttggacag aggtcccagt ttcaaaccct 18600 attctggtac ggcttacaac tccctggctc ctaaaggcgc tccaaataca tctcagtgga 18660 ttgcagaagg tgtaaaaaat acaactggtg aggaacacgt aacagaagag gaaaccaata 18720 ctactactta cacttttggc aatgctcctg taaaagctga agctgaaatt acaaaagaag 18780 gactcccagt aggtttggaa gtttcagatg aagaaagtaa accgatttat gctgataaaa 18840 catatcagcc agaacctcag ctgggagatg aaacttggac tgaccttgat ggaaaaaccg 18900 aaaagtatgg aggcagggct ctcaaacccg atactaagat gaaaccatgc tacgggtcct 18960 ttgccaaacc tactaatgtg aaaggcggtc aggcaaaaca aaaaacaacg gagcagccaa 19020 atcagaaagt cgaatatgat atcgacatgg agttttttga tgcggcatcg cagaaaacaa 19080 acttaagtcc taaaattgtc atgtatgcag aaaatgtaaa tttggaaact ccagacactc 19140 atgtagtgta caaacctgga acagaagaca caagttccga agctaatttg ggacaacaat 19200 ctatgcccaa cagacccaac tacattggct tcagagataa ctttattgga cttatgtact 19260 ataacagtac tggtaacatg ggggtgctgg ctggtcaagc gtctcagtta aatgcagtgg 19320 ttgacttgca ggacagaaac acagaacttt cttaccaact cttgcttgac tctctgggcg 19380 acagaaccag atactttagc atgtggaatc aggctgtgga cagttatgat cctgatgtac 19440 gtgttattga aaatcatggt gtggaagatg aacttcccaa ctactgtttt ccactggacg 19500 gcataggtgt tccaacaacc agttacaaat caatagttcc aaatggagac aatgcgccta 19560 attggaagga acctgaagta aatggaacaa gtgagatcgg acagggtaat ttgtttgcca 19620 tggaaattaa ccttcaagcc aatctatggc gaagtttcct ttattccaat gtggctctat 19680 atctcccaga ctcgtacaaa tacaccccgt ccaatgtcac tcttccagaa aacaaaaaca 19740 cctacgacta catgaacggg cgggtggtgc cgccatctct agtagacacc tatgtgaaca 19800 ttggtgccag gtggtctctg gatgccatgg acaatgtcaa cccattcaac caccaccgta 19860 acgctggctt gcgttaccga tccatgcttc tgggtaacgg acgttatgtg cctttccaca 19920 tacaagtgcc tcaaaaattc ttcgctgtta aaaacctgct gcttctccca ggctcctaca 19980 cttatgagtg gaactttagg aaggatgtga acatggttct acagagttcc ctcggtaacg 20040 acctgcgggt agatggcgcc agcatcagtt tcacgagcat caacctctat gctacttttt 20100 tccccatggc tcacaacacc gcttccaccc ttgaagccat gctgcggaat gacaccaatg 20160 atcagtcatt caacgactac ctatctgcag ctaacatgct ctaccccatt cctgccaatg 20220 caaccaatat tcccatttcc attccttctc gcaactgggc ggctttcaga ggctggtcat 20280 ttaccagact gaaaaccaaa gaaactccct ctttggggtc tggatttgac ccctactttg 20340 tctattctgg ttctattccc tacctggatg gtaccttcta cctgaaccac acttttaaga 20400 aggtttccat catgtttgac tcttcagtga gctggcctgg aaatgacagg ttactatctc 20460 ctaacgaatt tgaaataaag cgcactgtgg atggcgaagg ctacaacgta gcccaatgca 20520 acatgaccaa agactggttc ttggtacaga tgctcgccaa ctacaacatc ggctatcagg 20580 gcttctacat tccagaagga tacaaagatc gcatgtattc atttttcaga aacttccagc 20640 ccatgagcag gcaggtggtt gatgaggtca attacaaaga cttcaaggcc gtcgccatac 20700 cctaccaaca caacaactct ggctttgtgg gttacatggc tccgaccatg cgccaaggtc 20760 aaccctatcc cgctaactat ccctatccac tcattggaac aactgccgta aatagtgtta 20820 cgcagaaaaa gttcttgtgt gacagaacca tgtggcgcat accgttctcg agcaacttca 20880 tgtctatggg ggcccttaca gacttgggac agaatatgct ctatgccaac tcagctcatg 20940 ctctggacat gacctttgag gtggatccca tggatgagcc caccctgctt tatcttctct 21000 tcgaagtttt cgacgtggtc agagtgcatc agccacaccg cggcatcatc gaggcagtct 21060 acctgcgtac accgttctcg gccggtaacg ctaccacgta agaagcttct tgcttcttgc 21120 aaatagcagc tgcaaccatg gcctgcggat cccaaaacgg ctccagcgag caagagctca 21180 gagccattgt ccaagacctg ggttgcggac cctatttttt gggaacctac gataagcgct 21240 tcccggggtt catggccccc gataagctcg cctgtgccat tgtaaatacg gccggacgtg 21300 agacgggggg agagcactgg ttggctttcg gttggaaccc acgttctaac acctgctacc 21360 tttttgatcc ttttggattc tcggatgatc gtctcaaaca gatttaccag tttgaatatg 21420 agggtctcct gcgccgcagc gctcttgcta ccaaggaccg ctgtattacg ctggaaaaat 21480 ctacccagac cgtgcagggt ccccgttctg ccgcctgcgg acttttctgc tgcatgttcc 21540 ttcacgcctt tgtgcactgg cctgaccgtc ccatggacgg aaaccccacc atgaaattgc 21600 taactggagt gccaaacaac atgcttcatt ctcctaaagt ccagcccacc ctgtgtgaca 21660 atcaaaaagc actctaccat tttcttaata cccattcgcc ttattttcgc tcccatcgta 21720 cacacatcga aagggccact gcgttcgacc gtatggatgt tcaataatga ctcatgtaaa 21780 caacgtgttc aataaacatc actttatttt tttacatgta tcaaggctct gcattactta 21840 tttatttaca agtcgaatgg gttctgacga gaatcagaat gacccgcagg cagtgatacg 21900 ttgcggaact gatacttggg ttgccacttg aattcgggaa tcaccaactt gggaaccggt 21960 atatcgggca ggatgtcact ccacagcttt ctggtcagct gcaaagctcc aagcaggtca 22020 ggagccgaaa tcttgaaatc acaattagga ccagtgcttt gagcgcgaga gttgcggtac 22080 accggattgc agcactgaaa caccatcagc gacggatgtc tcacgcttgc cagcacggtg 22140 ggatctgcaa tcatgcccac atccagatct tcagcattgg caatgctgaa cggggtcatc 22200 ttgcaggtct gcctacccat ggcgggcacc caattaggct tgtggttgca atcgcagtgc 22260 agggggatca gtatcatctt ggcctgatcc tgtctgattc ctggatacac ggctctcatg 22320 aaagcatcat attgcttgaa agcctgctgg gctttactac cctcggtata aaacatcccg 22380 caggacctgc tcgaaaactg gttagctgca cagccggcat cattcacaca gcagcgggcg 22440 tcattgttag ctatttgcac cacacttctg ccccagcggt tttgggtgat tttggttcgc 22500 tcgggattct cctttaaggc tcgttgtccg ttctcgctgg ccacatccat ctcgataatc 22560 tgctccttct gaatcataat attgccatgc aggcacttca gcttgccctc ataatcattg 22620 cagccatgag gccacaacgc acagcctgta cattcccaat tatggtgggc gatctgagaa 22680 aaagaatgta tcattccctg cagaaatctt cccatcatcg tgctcagtgt cttgtgacta 22740 gtgaaagtta actggatgcc tcggtgctcc tcgtttacgt actggtgaca gatgcgcttg 22800 tattgttcgt gttgctcagg cattagttta aaagaggttc taagttcgtt atccagcctg 22860 tacttctcca tcagcagaca catcacttcc atgcctttct cccaagcaga caccaggggc 22920 aagctaatcg gattcttaac agtgcaggca gcagctcctt tagccagagg gtcatcttta 22980 gcgatcttct caatgcttct tttgccatcc ttctcaacga tgcgcacggg cgggtagctg 23040 aaacccactg ctacaagttg cgcctcttct ctttcttctt cgctgtcttg actgatgtct 23100 tgcatgggga tatgtttggt cttccttggc ttctttttgg ggggtatcgg aggaggagga 23160 ctgtcgctcc gttccggaga cagggaggat tgtgacgttt cgctcaccat taccaactga 23220 ctgtcggtag aagaacctga ccccacacgg cgacaggtgt ttctcttcgg gggcagaggt 23280 ggaggcgatt gcgaagggct gcggtccgac ctggaaggcg gatgactggc agaacccctt 23340 ccgcgttcgg gggtgtgctc cctgtggcgg tcgcttaact gatttccttc gcggctggcc 23400 attgtgttct cctaggcaga gaaacaacag acatggaaac tcagccattg ctgtcaacat 23460 cgccacgagt gccatcacat ctcgtcctca gcgacgagga aaaggagcag agcttaagca 23520 ttccaccgcc cagtcctgcc accacctcta ccctagaaga taaggaggtc gacgcatctc 23580 atgacatgca gaataaaaaa gcgaaagagt ctgagacaga catcgagcaa gacccgggct 23640 atgtgacacc ggtggaacac gaggaagagt tgaaacgctt tctagagaga gaggatgaaa 23700 actgcccaaa acaacgagca gataactatc accaagatgc tggaaatagg gatcagaaca 23760 ccgactacct catagggctt gacggggaag acgcgctcct taaacatcta gcaagacagt 23820 cgctcatagt caaggatgca ttattggaca gaactgaagt gcccatcagt gtggaagagc 23880 tcagccgcgc ctacgagctt aacctctttt cacctcgtac tccccccaaa cgtcagccaa 23940 acggcacctg cgagccaaat cctcgcttaa acttttatcc agcttttgct gtgccagaag 24000 tactggctac ctatcacatc ttttttaaaa atcaaaaaat tccagtctcc tgccgcgcta 24060 atcgcacccg cgccgatgcc ctactcaatc tgggacctgg ttcacgctta cctgatatag 24120 cttccttgga agaggttcca aagatcttcg agggtctggg caataatgag actcgggccg 24180 caaatgctct gcaaaaggga gaaaatggca tggatgagca tcacagcgtt ctggtggaat 24 240 tggaaggcga taatgccaga ctcgcagtac tcaagcgaag catcgaggtc acacacttcg 24300 catatcccgc tgtcaacctg ccccctaaag tcatgacggc ggtcatggac cagttactca 24360 ttaagcgcgc aagtcccctt tcagaagaca tgcatgaccc agatgcctgt gatgagggta 24420 aaccagtggt cagtgatgag cagctaaccc gatggctggg caccgactct cccagggatt 24480 tggaagagcg tcgcaagctt atgatggccg tggtgctggt taccgtagaa ctagagtgtc 24540 tccgacgttt ctttaccgat tcagaaacct tgcgcaaact cgaagagaat ctgcactaca 24600 cttttagaca cggctttgtg cggcaggcat gcaagatatc taacgtggaa ctcaccaacc 24660 tggtttccta catgggtatt ctgcatgaga atcgcctagg acaaagcgtg ctgcacagca 24720 ccctgaaggg ggaagcccgc cgtgattaca tccgcgattg tgtctatctg tacctgtgcc 24780 acacgtggca aaccggcatg ggtgtatggc agcaatgttt agaagaacag aacttgaaag 24840 agcttgacaa gctcttacag aaatctctta aggttctgtg gacagggttc gacgagcgca 24900 ccgtcgcttc cgacctggca gacctcatct tcccagagcg tctcagggtt actttgcgaa 24960 acggattgcc tgactttatg agccagagca tgcttaacaa ttttcgctct ttcatcctgg 25020 aacgctccgg tatcctgccc gccacctgct gcgcactgcc ctccgacttt gtgcctctca 25080 cctaccgcga gtgccccccg ccgctatgga gtcactgcta cctgttccgt ctggccaact 25 140 atctctccta ccactcggat gtgatcgagg atgtgagcgg agacggcttg ctggagtgtc 25200 actgccgctg caatctgtgc acgccccacc ggtccctagc ttgcaacccc cagttgatga 25260 gcgaaaccca gataataggc acctttgaat tgcaaggccc cagcagccaa ggcgatgggt 25320 cttctcctgg gcaaagttta aaactgaccc cgggactgtg gacctccgcc tacttgcgca 25380 agtttgctcc ggaagattac cacccctatg aaatcaagtt ctatgaggac caatcacagc 25440 ctccaaaggc cgaactttcg gcctgcgtca tcacccaggg ggcaattctg gcccaattgc 25500 aagccatcca aaaatcccgc caagaatttc tactgaaaaa gggtaagggg gtctaccttg 25560 acccccagac cggcgaggaa ctcaacacaa ggttccctca ggatgtccca acgacgagaa 25620 aacaagaagt tgaaggtgca gccgccgccc ccagaagata tggaggaaga ttgggacagt 25680 caggcagagg aggcggagga ggacagtctg gaggacagtc tggaggaaga cagtttggag 25740 gaggaaaacg aggaggcaga ggaggtggaa gaagtaaccg ccgacaaaca gttatcctcg 25800 gctgcggaga caagcaacag cgctaccatc tccgctccga gtcgaggaac ccggcggcgt 25860 cccagcagta gatgggacga gaccggacgc ttcccgaacc caaccagcgc ttccaagacc 25920 ggtaagaagg atcggcaggg atacaagtcc tggcgggggc ataagaatgc catcatctcc 25980 tgcttgcatg agtgcggggg caacatatcc ttcacgcggc gctacttgct attccaccat 26040 ggggtgaact ttccgcgcaa tgttttgcat tactaccgtc acctccacag cccctactat 26100 agccagcaaa tcccggcagt ctcgacagat aaagacagcg gcggcgacct ccaacagaaa 26160 accagcagcg gcagttagaa aatacacaac aagtgcagca acaggaggat taaagattac 26220 agccaacgag ccagcgcaaa cccgagagtt aagaaatcgg atctttccaa ccctgtatgc 26280 catcttccag cagagtcggg gtcaagagca ggaactgaaa ataaaaaacc gatctctgcg 26340 ttcgctcacc agaagttgtt tgtatcacaa gagcgaagat caacttcagc gcactctcga 26400 ggacgccgag gctctcttca acaagtactg cgcgctgact cttaaagagt aggcagcgac 26460 cgcgcttatt caaaaaaggc gggaattaca tcatcctcga catgagtaaa gaaattccca 26520 cgccttacat gtggagttat caaccccaaa tgggattggc ggcaggcgcc tcccaggact 26580 actccacccg catgaattgg ctcagcgccg ggccttctat gatttctcga gttaatgata 26640 tacgcgccta ccgaaaccaa atacttttgg aacagtcagc tcttaccacc acgccccgcc 26700 aacaccttaa tcccagaaat tggcccgccg ccctagtgta ccaggaaagt cccgctccca 26760 ccactgtatt acttcctcga gacgcccagg ccgaagtcca aatgactaat gcaggtgcgc 26820 agttagctgg cggctccacc ctatgtcgtc acaggcctcg gcataatata aaacgcctga 26880 tgatcagagg ccgaggtatc cagctcaacg acgagtcggt gagctctccg cttggtctac 26940 gaccagacgg aatctttcag attgccggct gcgggagatc ttccttcacc cctcgtcagg 27000 ctgttctgac tttggaaagt tcgtcttcgc aaccccgctc gggcggaatc gggaccgttc 27060 aatttgtgga ggagtttact ccctctgtct acttcaaccc cttctccgga tctcctgggc 27120 attacccgga cgagttcata ccgaacttcg acgcgattag cgagtcagtg gacggctacg 27180 attgatgtct ggtgacgcgg ctgagctatc tcggctgcga catctagacc actgccgccg 27240 ctttcgctgc tttgcccggg aactcattga gttcatctac ttcgaactcc ccaaggatca 27300 ccctcaaggt ccggcccacg gagtgcggat ttctatcgaa ggcaaaatag actctcgcct 27360 gcaacgaatt ttctcccagc ggcccgtgct gatcgagcga gaccagggaa acaccacggt 27420 ttccatctac tgcatttgta atcaccccgg attgcatgaa agcctttgct gtcttatgtg 27480 tactgagttt aataaaaact gaattaagac tctcctacgg actgccgctt cttcaacccg 27540 gattttacaa ccagaagaac gaaacttttc ctgtcgtcca ggactctgtt aacttcacct 27600 ttcctactca caaactagaa gctcaacgac tacaccgctt ttccagaagc attttcccta 27660 ctaatactac tttcaaaacc ggaggtgagc tccaaggtct tcctacagaa aacccttggg 27720 tggaagcggg ccttgtagtg ctaggaattc ttgcgggtgg gcttgtgatt attctttgct 27780 acctatacac accttgcttc actttcttag tggtgttgtg gtattggttt aaaaaatggg 27840 gcccatacta gtcttgcttg ttttactttc gcttttggaa ccgggttctg ccaattacga 27900 tccatgtcta gacttcgacc cagaaaactg cacacttact tttgcacccg acacaagccg 27960 catctgtgga gttcatcgcc tctcttacga acttggcccc caacgacaaa aatttacctg 28020 catggtggga atcaacccca tagttatcac ccagcaaagt ggagatacta agggttgcat 28080 tcactgctcc tgcgattcca tcgagtgcac ctacaccctg ctgaagaccc tatgcggcct 28140 aagagacctg ctaccaatga attaaaaaat gattaataaa aaatcactta cttgaaatca 28200 gcaataaggt ctctgttgaa attttctccc agcagcacct cacttccctc ttcccaactc 28260 tggtattcta aaccccgttc agcggcatac tttctccata ctttaaaggg gatgtcaaat 28320 tttagctcct ctcctgtacc cacaatcttc atgtctttct tcccagatga ccaagagagt 28380 ccggctcagt gactccttca accctgtcta cccctatgaa gatgaaagca cctcccaaca 28440 cccctttata aacccagggt ttatttcccc aaatggcttc acacaaagcc caaacggagt 28500 tcttacttta aaatgtttaa ccccactaac aaccacaggc ggatctctac agctaaaagt 28560 gggaggggga cttacagtgg atgacaccaa cggttttttg aaagaaaaca taagtgccac 28620 cacaccactc gttaagactg gtcactctat aggtttacca ctaggagccg gattgggaac 28680 gaatgaaaat aaactttgta tcaaattagg acaaggactt acattcaatt caaacaacat 28740 ttgcattgat gacaatatta acaccttatg gacaggagtc aaccccaccg aagccaactg 28800 tcaaatcatg aactccagtg aatctaatga ttgcaaatta attctaacac tagttaaaac 28860 tggagcacta gtcactgcat ttgtttatgt tataggagta tctaacaatt ttaatatgct 28920 aactacacac agaaatataa attttactgc agagctgttt ttcgattcta ctggtaattt 28980 actaactaga ctctcatccc tcaaaactcc acttaatcat aaatcaggac aaaacatggc 29040 tactggtgcc attactaatg ctaaaggttt catgcccagc acgactgcct atcctttcaa 29100 tgataattct agagaaaaag aaaactacat ttacggaact tgttactaca cagctagtga 29160 tcgcactgct tttcccattg acatatctgt catgcttaac cgaagagcaa taaatgacga 29220 gacatcatat tgtattcgta taacttggtc ctggaacaca ggagatgccc cagaggtgca 29280 aacctctgct acaaccctag tcacctcccc atttaccttt tactacatca gagaagacga 29340 ctgacaaata aagtttgcga tcgccaggcc caccatggga tggagctgta tcatcctctt 29400 cttggtagca acagctacag gtgtccactc ccaggtgcag ctgcagcagt ctggggctga 29460 actggcaaga cctggggcct cagtgaagat gtcctgcaag gcttctggct acacctttac 29520 taggtacacg atgcactggg taaaacagag gcctggacag ggtctggaat ggattggata 29580 cattaatcct agccgtggtt atactaatta caatcagaag ttcaaggaca aggccacatt 29640 gactacagac aaatcctcca gcacagccta catgcaactg agcagcctga catctgagga 29700 ctctgcagtc tattactgtg caagatatta tgatgatcat tactgccttg actactgggg 29760 ccaaggcacc actctcacag tctcctcagg tggcggtggc tcgggcggtg gtggatctgg 29820 tggcggcgga tctgatatcg tgctcactca gtctccagca atcatgtctg catctccagg 29880 ggagaaggtc accatgacct gcagtgccag ctcaagtgta agttacatga actggtacca 29940 gcagaagtca ggcacctccc ccaaaagatg gatttatgac acatccaaac tggcttctgg 30000 agtccctgct cacttcaggg gcagtgggtc tgggacctct tactctctca caatcagcgg 30060 catggaggct gaagatgctg ccacttatta ctgccagcag tggagtagta acccattcac 30120 gttcggctcg gggacaaagt tggaaataaa ccggggatcc gaacaaaaac tcatctcaga 30180 agaggatctg aatgctgtgg gccaggacac gcaggaggtc atcgtggtgc cacactcctt 30240 gccctttaag gtggtggtga tctcagccat cctggccctg gtggtgctca ccatcatctc 30300 ccttatcatc ctcatcatgc tttggcagaa gaagccacgt ggttcaatcc ctaaccctct 30360 cctcggtctc gattaagcta gcttgactga ctgagataca gcgtaccttc agctcacaga 30420 catgataaga tacattgatg agtttggaca aaccacaact agaatgcagt gaaaaaaatg 30480 ctttatttgt gaaatttgtg atgctattgc tttatttgta accattataa gctgcaataa 30540 acaagttaac aacaacaatt gcattcattt tatgtttcag gttcaggggg aggtgtggga 30600 ggttttttaa agcaagtaaa acctctacaa atgtggtagt cgtcagctat cctgcaggaa 30660 cttgtttatt tgaaaatcaa ttcacaaaat ccgagtagtt attttgcctc ccccttccca 30720 tttaacagaa tacaccaatc tctccccacg cacagcttta aacatttgga taccattaga 30780 tatagacatg gttttagatt ccacattcca aacagtttca gagcgagcca atctggggtc 30840 agtgatagat aaaaatccat cgggatagtc ttttaaagcg ctttcacagt ccaactgctg 30900 cggatgcgac tccggagtct ggatcacggt catctggaag aagaacgatg ggaatcataa 30960 tccgaaaacg gtatcggacg attgtgtctc atcaaaccca caagcagccg ctgtctgcgt 31020 cgctccgtgc gactgctgtt tatgggatca gggtccacag tgtcctgaag catgatttta 31080 atagccctta acatcaactt tctggtgcga tgcgcgcagc aacgcattct gatttcactc 31140 aaatctttgc agtaggtaca acacattatt acaatattgt ttaataaacc ataattaaaa 31200 gcgctccagc caaaactcat atctgatata atcgcccctg catgaccatc ataccaaagt 31260 ttaatataaa ttaaatgacg ttccctcaaa aacacactac ccacatacat gatctctttt 31320 ggcatgtgca tattaacaat ctgtctgtac catggacaac gttggttaat catgcaaccc 31380 aatataacct tccggaacca cactgccaac accgctcccc cagccatgca ttgaagtgaa 31440 ccctgctgat tacaatgaca atgaagaacc caattctctc gaccgtgaat cacttgagaa 31500 tgaaaaatat ctatagtggc acaacataga cataaatgca tgcatcttct cataattttt 31560 aactcctcag gatttagaaa catatcccag ggaataggaa gctcttgcag aacagtaaag 31620 ctggcagaac aaggaagacc acgaacacaa cttacactat gcatagtcat agtatcacaa 31680 tctggcaaca gcgggtggtc ttcagtcata gaagctcggg tttcattttc ctcacaacgt 31740 ggtaactggg ctctggtgta agggtgatgt ctggcgcatg atgtcgagcg tgcgcgcaac 31800 cttgtcataa tggagttgct tcctgacatt ctcgtatttt gtatagcaaa acgcggccct 31860 ggcagaacac actcttcttc gccttctatc ctgccgctta gcgtgttccg tgtgatagtt 31920 caagtacaac cacactctta agttggtcaa aagaatgctg gcttcagttg taatcaaaac 31980 tccatcgcat ctaatcgttc tgaggaaatc atccaagcaa tgcaactgga ttgtgtttca 32040 agcaggagag gagagggaag agacggaaga accatgttaa tttttattcc aaacgatctc 32 100 gcagtacttc aaattgtaga tcgcgcagat ggcatctctc gcccccactg tgttggtgaa 32160 aaagcacagc tagatcaaaa gaaatgcgat tttcaaggtg ctcaacggtg gcttccagca 32220 aagcctccac gcgcacatcc aagaacaaaa gaataccaaa agaaggagca ttttctaact 32280 cctcaatcat catattacat tcctgcacca ttcccagata attttcagct ttccagcctt 32340 gaattattcg tgtcagttct tgtggtaaat ccaatccaca cattacaaac aggtcccgga 32400 gggcgccctc caccaccatt cttaaacaca ccctcataat gacaaaatat cttgctcctg 32460 tgtcacctgt agcgaattga gaatggcaac atcaattgac atgcccttgg ctctaagttc 32520 ttctttaagt tctagttgta aaaactctct catattatca ccaaactgct tagccagaag 32580 ccccccggga acaagagcag gggacgctac agtgcagtac aagcgcagac ctccccaatt 32640 ggctccagca aaaacaagat tggaataagc atattgggaa ccgccagtaa tatcatcgaa 32700 gttgctggaa atataatcag gcagagtttc ttgtaaaaat tgaataaaag aaaaatttgc 32760 caaaaaaaca ttcaaaacct ctgggatgca aatgcaatag gttaccgcgc tgcgctccaa 32820 cattgttagt tttgaattag tctgcaaaaa taaaaaaaaa aacaagcgtc atatcatagt 32880 agcctgacga acagatggat aaatcagtct ttccatcaca agacaagcca cagggtctcc 32940 agctcgaccc tcgtaaaacc tgtcatcatg attaaacaac agcaccgaaa gttcctcgcg 33000 gtgaccagca tgaataattc ttgatgaagc atacaatcca gacatgttag catcagttaa 33060 cgagaaaaaa cagccaacat agcctttggg tataattatg cttaatcgta agtatagcaa 33 120 agccacccct cgcggataca aagtaaaagg cacaggagaa taaaaaatat aattatttct 33180 ctgctgctgt tcaggcaacg tcgcccccgg tccctctaaa tacacataca aagcctcatc 33 240 agccatggct taccagacaa agtacagcgg gcacacaaag cacaagctct aaagtgactc 33 300 tccaacctct ccacaatata tatatacaca agccctaaac tgacgtaatg ggagtaaagt 33 360 gtaaaaaatc ccgccaaacc caacacacac cccgaaactg cgtcaccagg gaaaagtaca 33420 gtttcacttc cgcaatccca acaggcgtaa cttcctcttt ctcacggtac gtgatatccc 33480 actaacttgc aacgtcattt tcccacggtc gcaccgcccc ttttagccgt taaccccaca 33540 gccaatcacc acacgatcca cactttttaa aatcacctca tttacatatt ggcaccattc 33600 catctataag gtatattata tagataga 33628 <210> 104 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Linker <400> 104 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 15 <210> 105 <211> 13 <212> RNA <213> Artificial Sequence <220> <223> Sequence comprising a start codon <400> 105 gccgccrcca ugg 13 <210> 106 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> c-myc tag <400> 106 Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu 1 5 10 <210> 107 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> c-myc tag with amino acid spacer at the N and C-terminal <400> 107 Gly Ser Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Asn 1 5 10 <210> 108 <211> 62 <212> PRT <213> Artificial Sequence <220> <223> spacer-c-myc tag -spacer PDGF TM domain <400> 108 Gly Ser Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Asn Ala Val Gly 1 5 10 15 Gln Asp Thr Gln Glu Val Ile Val Val Pro His Ser Leu Pro Phe Lys 20 25 30 Val Val Val Ile Ser Ala Ile Leu Ala Leu Val Val Leu Thr Ile Ile 35 40 45 Ser Leu Ile Ile Leu Ile Met Leu Trp Gln Lys Lys Pro Arg 50 55 60 <210> 109 <211> 32345 <212> DNA <213> Artificial Sequence <220> <223> Fully synthetic EnAd genome with incorporated cloning site for transgene cassette insertion as in plasmid pEnAd2.4 <400> 109 tctatctata taatatacct tatagatgga atggtgccaa tatgtaaatg aggtgatttt 60 aaaaagtgtg gatcgtgtgg tgattggctg tggggttaac ggctaaaagg ggcggtgcga 120 ccgtgggaaa atgacgtttt gtgggggtgg agtttttttg caagttgtcg cgggaaatgt 180 gacgcataaa aaggcttttt tctcacggaa ctacttagtt ttcccacggt atttaacagg 240 aaatgaggta gttttgaccg gatgcaagtg aaaattgttg attttcgcgc gaaaactgaa 300 tgaggaagtg tttttctgaa taatgtggta tttatggcag ggtggagtat ttgttcaggg 360 ccaggtagac tttgacccat tacgtggagg tttcgattac cgtgtttttt acctgaattt 420 ccgcgtaccg tgtcaaagtc ttctgttttt acgtaggtgt cagctgatcg ctagggtatt 480 tatacctcag ggtttgtgtc aagaggccac tcttgagtgc cagcgagaag agttttctcc 540 tctgcgccgg cagtttaata ataaaaaaat gagagatttg cgatttctgc ctcaggaaat 600 aatctctgct gagactggaa atgaaatatt ggagcttgtg gtgcacgccc tgatgggaga 660 cgatccggag ccacctgtgc agctttttga gcctcctacg cttcaggaac tgtatgattt 720 agaggtagag ggatcggagg attctaatga ggaagctgta aatggctttt ttaccgattc 780 tatgctttta gctgctaatg aagggttaga attagatccg cctttggaca cttttgatac 840 tccaggggta attgtggaaa gcggtacagg tgtaagaaaa ttacctgatt tgagttccgt 900 ggactgtgat ttgcactgct atgaagacgg gtttcctccg agtgatgagg aggaccatga 960 aaaggagcag tccatgcaga ctgcagcggg tgagggagtg aaggctgcca atgttggttt 1020 tcagttggat tgcccggagc ttcctggaca tggctgtaag tcttgtgaat ttcacaggaa 1080 aaatactgga gtaaaggaac tgttatgttc gctttgttat atgagaacgc actgccactt 1140 tatttacagt aagtgtgttt aagttaaaat ttaaaggaat atgctgtttt tcacatgtat 1200 attgagtgtg agttttgtgc ttcttattat aggtcctgtg tctgatgctg atgaatcacc 1260 atctcctgat tctactacct cacctcctga gattcaagca cctgttcctg tggacgtgcg 1320 caagcccatt cctgtgaagc ttaagcctgg gaaacgtcca gcagtggaaa aacttgagga 1380 cttgttacag ggtggggacg gacctttgga cttgagtaca cggaaacgtc caagacaata 1440 agtgttccat atccgtgttt acttaaggtg acgtcaatat ttgtgtgaca gtgcaatgta 1500 ataaaaatat gttaactgtt cactggtttt tattgctttt tgggcgggga ctcaggtata 1560 taagtagaag cagacctgtg tggttagctc ataggagctg gctttcatcc atggaggttt 1620 gggccatttt ggaagacctt aggaagacta ggcaactgtt agagaacgct tcggacggag 1680 tctccggttt ttggagattc tggttcgcta gtgaattagc tagggtagtt tttaggataa 1740 aacaggacta taaacaagaa tttgaaaagt tgttggtaga ttgcccagga ctttttgaag 1800 ctcttaattt gggccatcag gttcacttta aagaaaaagt tttatcagtt ttagactttt 1860 caaccccagg tagaactgct gctgctgtgg cttttcttac ttttatatta gataaatgga 1920 tcccgcagac tcatttcagc aggggatacg ttttggattt catagccaca gcattgtgga 1980 gaacatggaa ggttcgcaag atgaggacaa tcttaggtta ctggccagtg cagcctttgg 2040 gtgtagcggg aatcctgagg catccaccgg tcatgccagc ggttctggag gaggaacagc 2100 aagaggacaa cccgagagcc ggcctggacc ctccagtgga ggaggcggag tagctgactt 2160 gtctcctgaa ctgcaacggg tgcttactgg atctacgtcc actggacggg ataggggcgt 2220 taagagggag agggcatcta gtggtactga tgctagatct gagttggctt taagtttaat 2280 gagtcgcaga cgtcctgaaa ccatttggtg gcatgaggtt cagaaagagg gaagggatga 2340 agtttctgta ttgcaggaga aatattcact ggaacaggtg aaaacatgtt ggttggagcc 2400 tgaggatgat tgggaggtgg ccattaaaaa ttatgccaag atagctttga ggcctgataa 2460 acagtataag attactagac ggattaatat ccggaatgct tgttacatat ctggaaatgg 2520 ggctgaggtg gtaatagata ctcaagacaa ggcagttatt agatgctgca tgatggatat 2580 gtggcctggg gtagtcggta tggaagcagt aacttttgta aatgttaagt ttaggggaga 2640 tggttataat ggaatagtgt ttatggccaa taccaaactt atattgcatg gttgtagctt 2700 ttttggtttc aacaatacct gtgtagatgc ctggggacag gttagtgtac ggggatgtag 2760 tttctatgcg tgttggattg ccacagctgg cagaaccaag agtcaattgt ctctgaagaa 2820 atgcatattt caaagatgta acctgggcat tctgaatgaa ggcgaagcaa gggtccgcca 2880 ctgcgcttct acagatactg gatgttttat tttgattaag ggaaatgcca gcgtaaagca 2940 taacatgatt tgcggtgctt ccgatgagag gccttatcaa atgctcactt gtgctggtgg 3000 gcattgtaat atgctggcta ctgtgcatat tgtttcccat caacgcaaaa aatggcctgt 3060 ttttgatcac aatgtgatga cgaagtgtac catgcatgca ggtgggcgta gaggaatgtt 3120 tatgccttac cagtgtaaca tgaatcatgt gaaagtgttg ttggaaccag atgccttttc 3180 cagaatgagc ctaacaggaa tttttgacat gaacatgcaa atctggaaga tcctgaggta 3240 tgatgatacg agatcgaggg tacgcgcatg cgaatgcgga ggcaagcatg ccaggttcca 3300 gccggtgtgt gtagatgtga ctgaagatct cagaccggat catttggtta ttgcccgcac 3360 tggagcagag ttcggatcca gtggagaaga aactgactaa ggtgagtatt gggaaaactt 3420 tggggtggga ttttcagatg gacagattga gtaaaaattt gttttttctg tcttgcagct 3480 gtcatgagtg gaaacgcttc ttttaagggg ggagtcttca gcccttatct gacagggcgt 3540 ctcccatcct gggcaggagt tcgtcagaat gttatgggat ctactgtgga tggaagaccc 3600 gtccaacccg ccaattcttc aacgctgacc tatgctactt taagttcttc acctttggac 3660 gcagctgcag ctgccgccgc cgcttctgtt gccgctaaca ctgtgcttgg aatgggttac 3720 tatggaagca tcatggctaa ttccacttcc tctaataacc cttctaccct gactcaggac 3780 aagttacttg tccttttggc ccagctggag gctttgaccc aacgtctggg tgaactttct 3840 cagcaggtgg tcgagttgcg agtacaaact gagtctgctg tcggcacggc aaagtctaaa 3900 taaaaaaatc ccagaatcaa tgaataaata aacaagcttg ttgttgattt aaaatcaagt 3960 gtttttattt catttttcgc gcacggtatg ccctagacca ccgatctcta tcattgagaa 4020 ctcggtggat tttttccagg atcctataga ggtgggattg aatgtttaga tacatgggca 4080 ttaggccgtc tttggggtgg agatagctcc attgaaggga ttcatgctcc ggggtagtgt 4140 tgtaaatcac ccagtcataa caaggtcgca gtgcatggtg ttgcacaata tcttttagaa 4200 gtaggctgat tgccacagat aagcccttgg tgtaggtgtt tacaaaccgg ttgagctggg 4260 atgggtgcat tcggggtgaa attatgtgca ttttggattg gatttttaag ttggcaatat 4320 tgccgccaag atcccgtctt gggttcatgt tatgaaggac caccaagacg gtgtatccgg 4380 tacatttagg aaatttatcg tgcagcttgg atggaaaagc gtggaaaaat ttggagacac 4440 ccttgtgtcc tccaagattt tccatgcact catccatgat aatagcaatg gggccgtggg 4500 cagcggcgcg ggcaaacacg ttccgtgggt ctgacacatc atagttatgt tcctgagtta 4560 aatcatcata agccatttta atgaatttgg ggcggagagt accagattgg ggtatgaatg 4620 ttccttcggg ccccggagca tagttcccct cacagatttg catttcccaa gctttcagtt 4680 ccgagggtgg aatcatgtcc acctgggggg ctatgaaaaa caccgtttct ggggcggggg 4740 tgattaattg tgatgatagc aaatttctga gcaattgaga tttgccacat ccggtggggc 4800 cataaatgat tccgattacg ggttgcaggt ggtagtttag ggaacggcaa ctgccgtctt 4860 ctcgaagcaa gggggccacc tcgttcatca tttcccttac atgcatattt tcccgcacca 4920 aatccattag gaggcgctct cctcctagtg atagaagttc ttgtagtgag gaaaagtttt 4980 tcagcggttt cagaccgtca gccatgggca ttttggagag agtttgctgc aaaagttcta 5040 gtctgttcca cagttcagtg atgtgttcta tggcatctcg atccagcaga cctcctcgtt 5100 tcgcgggttt ggacggctcc tggaataggg tatgagacga tgggcgtcca gcgctgccag 5160 ggttcggtcc ttccagggtc tcagtgttcg agtcagggtt gtttccgtca cagtgaaggg 5220 gtgtgcgcct gcttgggcgc ttgccagggt gcgcttcaga ctcatcctgc tggtcgaaaa 5280 cttctgtcgc ttggcgccct gtatgtcggc caagtagcag tttaccatga gttcgtagtt 5340 gagcgcctcg gctgcgtggc ctttggcgcg gagcttacct ttggaagttt tcttgcatac 5400 cgggcagtat aggcatttca gcgcatacaa cttgggcgca aggaaaacgg attctgggga 5460 gtatgcatct gcgccgcagg aggcgcaaac agtttcacat tccaccagcc aggttaaatc 5520 cggttcattg gggtcaaaaa caagttttcc gccatatttt ttgatgcgtt tcttaccttt 5580 ggtctccatg agttcgtgtc ctcgttgagt gacaaacagg ctgtccgtgt ccccgtagac 5640 tgattttaca ggcctcttct ccagtggagt gcctcggtct tcttcgtaca ggaactctga 5700 ccactctgat acaaaggcgc gcgtccaggc cagcacaaag gaggctatgt gggaggggta 5760 gcgatcgttg tcaaccaggg ggtccacctt ttccaaagta tgcaaacaca tgtcaccctc 5820 ttcaacatcc aggaatgtga ttggcttgta ggtgtatttc acgtgacctg gggtccccgc 5880 tgggggggta taaaaggggg cggttctttg ctcttcctca ctgtcttccg gatcgctgtc 5940 caggaacgtc agctgttggg gtaggtattc cctctcgaag gcgggcatga cctctgcact 6000 caggttgtca gtttctaaga acgaggagga tttgatattg acagtgccgg ttgagatgcc 6060 tttcatgagg ttttcgtcca tctggtcaga aaacacaatt tttttattgt caagtttggt 6120 ggcaaatgat ccatacaggg cgttggataa aagtttggca atggatcgca tggtttggtt 6180 cttttccttg tccgcgcgct ctttggcggc gatgttgagt tggacatact cgcgtgccag 6240 gcacttccat tcggggaaga tagttgttaa ttcatctggc acgattctca cttgccaccc 6300 tcgattatgc aaggtaatta aatccacact ggtggccacc tcgcctcgaa ggggttcatt 6360 ggtccaacag agcctacctc ctttcctaga acagaaaggg ggaagtgggt ctagcataag 6420 ttcatcggga gggtctgcat ccatggtaaa gattcccgga agtaaatcct tatcaaaata 6480 gctgatggga gtggggtcat ctaaggccat ttgccattct cgagctgcca gtgcgcgctc 6540 atatgggtta aggggactgc cccatggcat gggatgggtg agtgcagagg catacatgcc 6600 acagatgtca tagacgtaga tgggatcctc aaagatgcct atgtaggttg gatagcatcg 6660 cccccctctg atacttgctc gcacatagtc atatagttca tgtgatggcg ctagcagccc 6720 cggacccaag ttggtgcgat tgggtttttc tgttctgtag acgatctggc gaaagatggc 6780 gtgagaattg gaagagatgg tgggtctttg aaaaatgttg aaatgggcat gaggtagacc 6840 tacagagtct ctgacaaagt gggcataaga ttcttgaagc ttggttacca gttcggcggt 6900 gacaagtacg tctagggcgc agtagtcaag tgtttcttga atgatgtcat aacctggttg 6960 gtttttcttt tcccacagtt cgcggttgag aaggtattct tcgcgatcct tccagtactc 7020 ttctagcgga aacccgtctt tgtctgcacg gtaagatcct agcatgtaga actgattaac 7080 tgccttgtaa gggcagcagc ccttctctac gggtagagag tatgcttgag cagcttttcg 7140 tagcgaagcg tgagtaaggg caaaggtgtc tctgaccatg actttgagga attggtattt 7200 gaagtcgatg tcgtcacagg ctccctgttc ccagagttgg aagtctaccc gtttcttgta 7260 ggcggggttg ggcaaagcga aagtaacatc attgaagaga atcttgccgg ccctgggcat 7320 gaaattgcga gtgatgcgaa aaggctgtgg tacttccgct cggttattga taacctgggc 7380 agctaggacg atctcgtcga aaccgttgat gttgtgtcct acgatgtata attctatgaa 7440 acgcggcgtg cctctgacgt gaggtagctt actgagctca tcaaaggtta ggtctgtggg 7500 gtcagataag gcgtagtgtt cgagagccca ttcgtgcagg tgaggattcg ctttaaggaa 7560 ggaggaccag aggtccactg ccagtgctgt ttgtaactgg tcccggtact gacgaaaatg 7620 ccgtccgact gccatttttt ctggggtgac gcaatagaag gtttgggggt cctgccgcca 7680 gcgatcccac ttgagtttta tggcgaggtc ataggcgatg ttgacgagcc gctggtctcc 7740 agagagtttc atgaccagca tgaaggggat tagctgcttg ccaaaggacc ccatccaggt 7800 gtaggtttcc acatcgtagg tgagaaagag cctttctgtg cgaggatgag agccaatcgg 7860 gaagaactgg atctcctgcc accagttgga ggaatggctg ttgatgtgat ggaagtagaa 7920 ctccctgcga cgcgccgagc attcatgctt gtgcttgtac agacggccgc agtagtcgca 7980 gcgttgcacg ggttgtatct cgtgaatgag ttgtacctgg cttcccttga cgagaaattt 8040 cagtgggaag ccgaggcctg gcgattgtat ctcgtgcttt actatgttgt ctgcatcggc 8100 ctgttcatct tctgtctcga tggtggtcat gctgacgagc cctcgcggga ggcaagtcca 8160 gacctcggcg cggcaggggc ggagctcgag gacgagagcg cgcaggctgg agctgtccag 8220 ggtcctgaga cgctgcggac tcaggttagt aggcagtgtc aggagattaa cttgcatgat 8280 cttttggagg gcgtgcggga ggttcagata gtacttgatc tcaacgggtc cgttggtgga 8340 gatgtcgatg gcttgcaggg ttccgtgtcc cttgggcgct accaccgtgc ccttgttttt 8400 cattttggac ggcggtggct ctgttgcttc ttgcatgttt agaagcggtg tcgagggcgc 8460 gcaccgggcg gcaggggcgg ctcgggaccc ggcggcatgg ctggcagtgg tacgtcggcg 8520 ccgcgcgcgg gtaggttctg gtactgcgcc ctgagaagac tcgcatgcgc gacgacgcgg 8580 cggttgacat cctggatctg acgcctctgg gtgaaagcta ccggccccgt gagcttgaac 8640 ctgaaagaga gttcaacaga atcaatctcg gtatcgttga cggcggcttg cctaaggatt 8700 tcttgcacgt caccagagtt gtcctggtag gcgatctccg ccatgaactg ctcgatctct 8760 tcctcttgaa gatctccgcg gcccgctctc tcgacggtgg ccgcgaggtc gttggagatg 8820 cgcccaatga gttgagagaa tgcattcatg cccgcctcgt tccagacgcg gctgtagacc 8880 acggccccca cgggatctct cgcgcgcatg accacctggg cgaggttgag ctccacgtgg 8940 cgggtgaaga ccgcatagtt gcataggcgc tggaaaaggt agttgagtgt ggtggcgatg 9000 tgctcggtga cgaagaaata catgatccat cgtctcagcg gcatctcgct gacatcgccc 9060 agagcttcca agcgctccat ggcctcgtag aagtccacgg caaaattaaa aaactgggag 9120 tttcgcgcgg acacggtcaa ctcctcttcc agaagacgga taagttcggc gatggtggtg 9180 cgcacctcgc gctcgaaagc ccctgggatt tcttcctcaa tctcttcttc ttccactaac 9240 atctcttcct cttcaggtgg ggctgcagga ggagggggaa cgcggcgacg ccggcggcgc 9300 acgggcagac ggtcgatgaa tctttcaatg acctctccgc ggcggcggcg catggtttca 9360 gtgacggcgc ggccgttctc gcgcggtcgc agagtaaaaa caccgccgcg catctcctta 9420 aagtggtgac tgggaggttc tccgtttggg agggagaggg cgctgattat acattttatt 9480 aattggcccg tagggactgc acgcagagat ctgatcgtgt caagatccac gggatctgaa 9540 aacctttcga cgaaagcgtc taaccagtca cagtcacaag gtaggctgag tacggcttct 9600 tgtgggcggg ggtggttatg tgttcggtct gggtcttctg tttcttcttc atctcgggaa 9660 ggtgagacga tgctgctggt gatgaaatta aagtaggcag ttctaagacg gcggatggtg 9720 gcgaggagca ccaggtcttt gggtccggct tgctggatac gcaggcgatt ggccattccc 9780 caagcattat cctgacatct agcaagatct ttgtagtagt cttgcatgag ccgttctacg 9840 ggcacttctt cctcacccgt tctgccatgc atacgtgtga gtccaaatcc gcgcattggt 9900 tgtaccagtg ccaagtcagc tacgactctt tcggcgagga tggcttgctg tacttgggta 9960 agggtggctt gaaagtcatc aaaatccaca aagcggtggt aagctcctgt attaatggtg 10020 taagcacagt tggccatgac tgaccagtta actgtctggt gaccagggcg cacgagctcg 10080 gtgtatttaa ggcgcgaata ggcgcgggtg tcaaagatgt aatcgttgca ggtgcgcacc 10140 agatactggt accctataag aaaatgcggc ggtggttggc ggtagagagg ccatcgttct 10200 gtagctggag cgccaggggc gaggtcttcc aacataaggc ggtgatagcc gtagatgtac 10260 ctggacatcc aggtgattcc tgcggcggta gtagaagccc gaggaaactc gcgtacgcgg 10320 ttccaaatgt tgcgtagcgg catgaagtag ttcattgtag gcacggtttg accagtgagg 10380 cgcgcgcagt cattgatgct ctatagacac ggagaaaatg aaagcgttca gcgactcgac 10440 tccgtagcct ggaggaacgt gaacgggttg ggtcgcggtg taccccggtt cgagacttgt 10500 actcgagccg gccggagccg cggctaacgt ggtattggca ctcccgtctc gacccagcct 10560 acaaaaatcc aggatacgga atcgagtcgt tttgctggtt tccgaatggc agggaagtga 10620 gtcctatttt ttttttttgc cgctcagatg catcccgtgc tgcgacagat gcgcccccaa 10680 caacagcccc cctcgcagca gcagcagcag caatcacaaa aggctgtccc tgcaactact 10740 gcaactgccg ccgtgagcgg tgcgggacag cccgcctatg atctggactt ggaagagggc 10800 gaaggactgg cacgtctagg tgcgccttca cccgagcggc atccgcgagt tcaactgaaa 10860 aaagattctc gcgaggcgta tgtgccccaa cagaacctat ttagagacag aagcggcgag 10920 gagccggagg agatgcgagc ttcccgcttt aacgcgggtc gtgagctgcg tcacggtttg 10980 gaccgaagac gagtgttgcg ggacgaggat ttcgaagttg atgaaatgac agggatcagt 11040 cctgccaggg cacacgtggc tgcagccaac cttgtatcgg cttacgagca gacagtaaag 11 100 gaagagcgta acttccaaaa gtcttttaat aatcatgtgc gaaccctgat tgcccgcgaa 11160 gaagttaccc ttggtttgat gcatttgtgg gatttgatgg aagctatcat tcagaaccct 11220 actagcaaac ctctgaccgc ccagctgttt ctggtggtgc aacacagcag agacaatgag 11280 gctttcagag aggcgctgct gaacatcacc gaacccgagg ggagatggtt gtatgatctt 11340 atcaacattc tacagagtat catagtgcag gagcggagcc tgggcctggc cgagaaggtg 11400 gctgccatca attactcggt tttgagcttg ggaaaatatt acgctcgcaa aatctacaag 11460 actccatacg ttcccataga caaggaggtg aagatagatg ggttctacat gcgcatgacg 11520 ctcaaggtct tgaccctgag cgatgatctt ggggtgtatc gcaatgacag aatgcatcgc 11580 gcggttagcg ccagcaggag gcgcgagtta agcgacaggg aactgatgca cagtttgcaa 11640 agagctctga ctggagctgg aaccgagggt gagaattact tcgacatggg agctgacttg 11700 cagtggcagc ctagtcgcag ggctctgagc gccgcgacgg caggatgtga gcttccttac 11760 atagaagagg cggatgaagg cgaggaggaa gagggcgagt acttggaaga ctgatggcac 11820 aacccgtgtt ttttgctaga tggaacagca agcaccggat cccgcaatgc gggcggcgct 11880 gcagagccag ccgtccggca ttaactcctc ggacgattgg acccaggcca tgcaacgtat 11940 catggcgttg acgactcgca accccgaagc ctttagacag caaccccagg ccaaccgtct 12000 atcggccatc atggaagctg tagtgccttc ccgctctaat cccactcatg agaaggtcct 12060 ggccatcgtg aacgcgttgg tggagaacaa agctattcgt ccagatgagg ccggactggt 12120 atacaacgct ctcttagaac gcgtggctcg ctacaacagt agcaatgtgc aaaccaattt 12180 ggaccgtatg ataacagatg tacgcgaagc cgtgtctcag cgcgaaaggt tccagcgtga 12240 tgccaacctg ggttcgctgg tggcgttaaa tgctttcttg agtactcagc ctgctaatgt 12300 gccgcgtggt caacaggatt atactaactt tttaagtgct ttgagactga tggtatcaga 12360 agtacctcag agcgaagtgt atcagtccgg tcctgattac ttctttcaga ctagcagaca 12420 gggcttgcag acggtaaatc tgagccaagc ttttaaaaac cttaaaggtt tgtggggagt 12480 gcatgccccg gtaggagaaa gagcaaccgt gtctagcttg ttaactccga actcccgcct 12540 attattactg ttggtagctc ctttcaccga cagcggtagc atcgaccgta attcctattt 12600 gggttaccta ctaaacctgt atcgcgaagc catagggcaa agtcaggtgg acgagcagac 12660 ctatcaagaa attacccaag tcagtcgcgc tttgggacag gaagacactg gcagtttgga 12720 agccactctg aacttcttgc ttaccaatcg gtctcaaaag atccctcctc aatatgctct 12780 tactgcggag gaggagagga tccttagata tgtgcagcag agcgtgggat tgtttctgat 12840 gcaagagggg gcaactccga ctgcagcact ggacatgaca gcgcgaaata tggagcccag 12900 catgtatgcc agtaaccgac ctttcattaa caaactgctg gactacttgc acagagctgc 12960 cgctatgaac tctgattatt tcaccaatgc catcttaaac ccgcactggc tgcccccacc 13020 tggtttctac acgggcgaat atgacatgcc cgaccctaat gacggatttc tgtgggacga 13080 cgtggacagc gatgtttttt cacctctttc tgatcatcgc acgtggaaaa aggaaggcgg 13140 cgatagaatg cattcttctg catcgctgtc cggggtcatg ggtgctaccg cggctgagcc 13200 cgagtctgca agtccttttc ctagtctacc cttttctcta cacagtgtac gtagcagcga 13260 agtgggtaga ataagtcgcc cgagtttaat gggcgaagag gagtatctaa acgattcctt 13320 gctcagaccg gcaagagaaa aaaatttccc aaacaatgga atagaaagtt tggtggataa 13380 aatgagtaga tggaagactt atgctcagga tcacagagac gagcctggga tcatggggat 13440 tacaagtaga gcgagccgta gacgccagcg ccatgacaga cagaggggtc ttgtgtggga 13500 cgatgaggat tcggccgatg atagcagcgt gctggacttg ggtgggagag gaaggggcaa 13560 cccgtttgct catttgcgcc ctcgcttggg tggtatgttg taaaaaaaaa taaaaaaaaa 13620 actcaccaag gccatggcga cgagcgtacg ttcgttcttc tttattatct gtgtctagta 13680 taatgaggcg agtcgtgcta ggcggagcgg tggtgtatcc ggagggtcct cctccttcgt 13740 acgagagcgt gatgcagcag cagcaggcga cggcggtgat gcaatcccca ctggaggctc 13800 cctttgtgcc tccgcgatac ctggcaccta cggagggcag aaacagcatt cgttattcgg 13860 aactggcacc tcagtacgat accaccaggt tgtatctggt ggacaacaag tcggcggaca 13920 ttgcttctct gaactatcag aatgaccaca gcaacttctt gaccacggtg gtgcaaaaca 13980 atgactttac ccctacggaa gccagcaccc agaccattaa ctttgatgaa cgatcgcggt 14040 ggggcggtca gctaaagacc atcatgcata ctaacatgcc aaacgtgaac gagtatatgt 14100 ttagtaacaa gttcaaagcg cgtgtgatgg tgtccagaaa acctcccgac ggtgctgcag 14160 ttggggatac ttatgatcac aagcaggata ttttgaaata tgagtggttc gagtttactt 14220 tgccagaagg caacttttca gttactatga ctattgattt gatgaacaat gccatcatag 14280 ataattactt gaaagtgggt agacagaatg gagtgcttga aagtgacatt ggtgttaagt 14340 tcgacaccag gaacttcaag ctgggatggg atcccgaaac caagttgatc atgcctggag 14400 tgtatacgta tgaagccttc catcctgaca ttgtcttact gcctggctgc ggagtggatt 14460 ttaccgagag tcgtttgagc aaccttcttg gtatcagaaa aaaacagcca tttcaagagg 14520 gttttaagat tttgtatgaa gatttagaag gtggtaatat tccggccctc ttggatgtag 14580 atgcctatga gaacagtaag aaagaacaaa aagccaaaat agaagctgct acagctgctg 14640 cagaagctaa ggcaaacata gttgccagcg actctacaag ggttgctaac gctggagagg 14700 tcagaggaga caattttgcg ccaacacctg ttccgactgc agaatcatta ttggccgatg 14760 tgtctgaagg aacggacgtg aaactcacta ttcaacctgt agaaaaagat agtaagaata 14820 gaagctataa tgtgttggaa gacaaaatca acacagccta tcgcagttgg tatctttcgt 14880 acaattatgg cgatcccgaa aaaggagtgc gttcctggac attgctcacc acctcagatg 14940 tcacctgcgg agcagagcag gtctactggt cgcttccaga catgatgaag gatcctgtca 15000 ctttccgctc cactagacaa gtcagtaact accctgtggt gggtgcagag cttatgcccg 15060 tcttctcaaa gagcttctac aacgaacaag ctgtgtactc ccagcagctc cgccagtcca 15120 cctcgcttac gcacgtcttc aaccgctttc ctgagaacca gattttaatc cgtccgccgg 15180 cgcccaccat taccaccgtc agtgaaaacg ttcctgctct cacagatcac gggaccctgc 15240 cgttgcgcag cagtatccgg ggagtccaac gtgtgaccgt tactgacgcc agacgccgca 15300 cctgtcccta cgtgtacaag gcactgggca tagtcgcacc gcgcgtcctt tcaagccgca 15360 ctttctaaaa aaaaaaaaaa tgtccattct tatctcgccc agtaataaca ccggttgggg 15420 tctgcgcgct ccaagcaaga tgtacggagg cgcacgcaaa cgttctaccc aacatcctgt 15480 ccgtgttcgc ggacattttc gcgctccatg gggcgccctc aagggccgca ctcgcgttcg 15540 aaccaccgtc gatgatgtaa tcgatcaggt ggttgccgac gcccgtaatt atactcctac 15600 tgcgcctaca tctactgtgg atgcagttat tgacagtgta gtggctgacg ctcgcaacta 15660 tgctcgacgt aagagccggc gaaggcgcat tgccagacgc caccgagcta ccactgccat 15720 gcgagccgca agagctctgc tacgaagagc tagacgcgtg gggcgaagag ccatgcttag 15780 ggcggccaga cgtgcagctt cgggcgccag cgccggcagg tcccgcaggc aagcagccgc 15840 tgtcgcagcg gcgactattg ccgacatggc ccaatcgcga agaggcaatg tatactgggt 15900 gcgtgacgct gccaccggtc aacgtgtacc cgtgcgcacc cgtccccctc gcacttagaa 15960 gatactgagc agtctccgat gttgtgtccc agcggcgagg atgtccaagc gcaaatacaa 16020 ggaagaaatg ctgcaggtta tcgcacctga agtctacggc caaccgttga aggatgaaaa 16080 aaaaccccgc aaaatcaagc gggttaaaaa ggacaaaaaa gaagaggaag atggcgatga 16140 tgggctggcg gagtttgtgc gcgagtttgc cccacggcga cgcgtgcaat ggcgtgggcg 16200 caaagttcga catgtgttga gacctggaac ttcggtggtc tttacacccg gcgagcgttc 16260 aagcgctact tttaagcgtt cctatgatga ggtgtacggg gatgatgata ttcttgagca 16320 ggcggctgac cgattaggcg agtttgctta tggcaagcgt agtagaataa cttccaagga 16380 tgagacagtg tcgataccct tggatcatgg aaatcccacc cctagtctta aaccggtcac 16440 tttgcagcaa gtgttacccg taactccgcg aacaggtgtt aaacgcgaag gtgaagattt 16500 gtatcccact atgcaactga tggtacccaa acgccagaag ttggaggacg ttttggagaa 16560 agtaaaagtg gatccagata ttcaacctga ggttaaagtg agacccatta agcaggtagc 16620 gcctggtctg ggggtacaaa ctgtagacat taagattccc actgaaagta tggaagtgca 16680 aactgaaccc gcaaagccta ctgccacctc cactgaagtg caaacggatc catggatgcc 16740 catgcctatt acaactgacg ccgccggtcc cactcgaaga tcccgacgaa agtacggtcc 16800 agcaagtctg ttgatgccca attatgttgt acacccatct attattccta ctcctggtta 16860 ccgaggcact cgctactatc gcagccgaaa cagtacctcc cgccgtcgcc gcaagacacc 16920 tgcaaatcgc agtcgtcgcc gtagacgcac aagcaaaccg actcccggcg ccctggtgcg 16980 gcaagtgtac cgcaatggta gtgcggaacc tttgacactg ccgcgtgcgc gttaccatcc 17040 gagtatcatc acttaatcaa tgttgccgct gcctccttgc agatatggcc ctcacttgtc 17100 gccttcgcgt tcccatcact ggttaccgag gaagaaactc gcgccgtaga agagggatgt 17160 tgggacgcgg aatgcgacgc tacaggcgac ggcgtgctat ccgcaagcaa ttgcggggtg 17220 gttttttacc agccttaatt ccaattatcg ctgctgcaat tggcgcgata ccaggcatag 17280 cttccgtggc ggttcaggcc tcgcaacgac attgacattg gaaaaaaacg tataaataaa 17340 aaaaaaaaaa tacaatggac tctgacactc ctggtcctgt gactatgttt tcttagagat 17400 ggaagacatc aatttttcat ccttggctcc gcgacacggc acgaagccgt acatgggcac 17460 ctggagcgac atcggcacga gccaactgaa cgggggcgcc ttcaattgga gcagtatctg 17520 gagcgggctt aaaaattttg gctcaaccat aaaaacatac gggaacaaag cttggaacag 17580 cagtacagga caggcgctta gaaataaact taaagaccag aacttccaac aaaaagtagt 17640 cgatgggata gcttccggca tcaatggagt ggtagatttg gctaaccagg ctgtgcagaa 17700 aaagataaac agtcgtttgg acccgccgcc agcaacccca ggtgaaatgc aagtggagga 17760 agaaattcct ccgccagaaa aacgaggcga caagcgtccg cgtcccgatt tggaagagac 17820 gctggtgacg cgcgtagatg aaccgccttc ttatgaggaa gcaacgaagc ttggaatgcc 17880 caccactaga ccgatagccc caatggccac cggggtgatg aaaccttctc agttgcatcg 17940 acccgtcacc ttggatttgc cccctccccc tgctgctact gctgtacccg cttctaagcc 18000 tgtcgctgcc ccgaaaccag tcgccgtagc caggtcacgt cccgggggcg ctcctcgtcc 18060 aaatgcgcac tggcaaaata ctctgaacag catcgtgggt ctaggcgtgc aaagtgtaaa 18 120 acgccgtcgc tgcttttaat taaatatgga gtagcgctta acttgcctat ctgtgtatat 18180 gtgtcattac acgccgtcac agcagcagag gaaaaaagga agaggtcgtg cgtcgacgct 18240 gagttacttt caagatggcc accccatcga tgctgcccca atgggcatac atgcacatcg 18300 ccggacagga tgcttcggag tacctgagtc cgggtctggt gcagttcgcc cgcgccacag 18360 acacctactt caatctggga aataagttta gaaatcccac cgtagcgccg acccacgatg 18420 tgaccaccga ccgtagccag cggctcatgt tgcgcttcgt gcccgttgac cgggaggaca 18480 atacatactc ttacaaagtg cggtacaccc tggccgtggg cgacaacaga gtgctggata 18540 tggccagcac gttctttgac attaggggtg tgttggacag aggtcccagt ttcaaaccct 18600 attctggtac ggcttacaac tccctggctc ctaaaggcgc tccaaataca tctcagtgga 18660 ttgcagaagg tgtaaaaaat acaactggtg aggaacacgt aacagaagag gaaaccaata 18720 ctactactta cacttttggc aatgctcctg taaaagctga agctgaaatt acaaaagaag 18780 gactcccagt aggtttggaa gtttcagatg aagaaagtaa accgatttat gctgataaaa 18840 catatcagcc agaacctcag ctgggagatg aaacttggac tgaccttgat ggaaaaaccg 18900 aaaagtatgg aggcagggct ctcaaacccg atactaagat gaaaccatgc tacgggtcct 18960 ttgccaaacc tactaatgtg aaaggcggtc aggcaaaaca aaaaacaacg gagcagccaa 19020 atcagaaagt cgaatatgat atcgacatgg agttttttga tgcggcatcg cagaaaacaa 19080 acttaagtcc taaaattgtc atgtatgcag aaaatgtaaa tttggaaact ccagacactc 19140 atgtagtgta caaacctgga acagaagaca caagttccga agctaatttg ggacaacaat 19200 ctatgcccaa cagacccaac tacattggct tcagagataa ctttattgga cttatgtact 19260 ataacagtac tggtaacatg ggggtgctgg ctggtcaagc gtctcagtta aatgcagtgg 19320 ttgacttgca ggacagaaac acagaacttt cttaccaact cttgcttgac tctctgggcg 19380 acagaaccag atactttagc atgtggaatc aggctgtgga cagttatgat cctgatgtac 19440 gtgttattga aaatcatggt gtggaagatg aacttcccaa ctactgtttt ccactggacg 19500 gcataggtgt tccaacaacc agttacaaat caatagttcc aaatggagac aatgcgccta 19560 attggaagga acctgaagta aatggaacaa gtgagatcgg acagggtaat ttgtttgcca 19620 tggaaattaa ccttcaagcc aatctatggc gaagtttcct ttattccaat gtggctctat 19680 atctcccaga ctcgtacaaa tacaccccgt ccaatgtcac tcttccagaa aacaaaaaca 19740 cctacgacta catgaacggg cgggtggtgc cgccatctct agtagacacc tatgtgaaca 19800 ttggtgccag gtggtctctg gatgccatgg acaatgtcaa cccattcaac caccaccgta 19860 acgctggctt gcgttaccga tccatgcttc tgggtaacgg acgttatgtg cctttccaca 19920 tacaagtgcc tcaaaaattc ttcgctgtta aaaacctgct gcttctccca ggctcctaca 19980 cttatgagtg gaactttagg aaggatgtga acatggttct acagagttcc ctcggtaacg 20040 acctgcgggt agatggcgcc agcatcagtt tcacgagcat caacctctat gctacttttt 20100 tccccatggc tcacaacacc gcttccaccc ttgaagccat gctgcggaat gacaccaatg 20160 atcagtcatt caacgactac ctatctgcag ctaacatgct ctaccccatt cctgccaatg 20220 caaccaatat tcccatttcc attccttctc gcaactgggc ggctttcaga ggctggtcat 20280 ttaccagact gaaaaccaaa gaaactccct ctttggggtc tggatttgac ccctactttg 20340 tctattctgg ttctattccc tacctggatg gtaccttcta cctgaaccac acttttaaga 20400 aggtttccat catgtttgac tcttcagtga gctggcctgg aaatgacagg ttactatctc 20460 ctaacgaatt tgaaataaag cgcactgtgg atggcgaagg ctacaacgta gcccaatgca 20520 acatgaccaa agactggttc ttggtacaga tgctcgccaa ctacaacatc ggctatcagg 20580 gcttctacat tccagaagga tacaaagatc gcatgtattc atttttcaga aacttccagc 20640 ccatgagcag gcaggtggtt gatgaggtca attacaaaga cttcaaggcc gtcgccatac 20700 cctaccaaca caacaactct ggctttgtgg gttacatggc tccgaccatg cgccaaggtc 20760 aaccctatcc cgctaactat ccctatccac tcattggaac aactgccgta aatagtgtta 20820 cgcagaaaaa gttcttgtgt gacagaacca tgtggcgcat accgttctcg agcaacttca 20880 tgtctatggg ggcccttaca gacttgggac agaatatgct ctatgccaac tcagctcatg 20940 ctctggacat gacctttgag gtggatccca tggatgagcc caccctgctt tatcttctct 21000 tcgaagtttt cgacgtggtc agagtgcatc agccacaccg cggcatcatc gaggcagtct 21060 acctgcgtac accgttctcg gccggtaacg ctaccacgta agaagcttct tgcttcttgc 21120 aaatagcagc tgcaaccatg gcctgcggat cccaaaacgg ctccagcgag caagagctca 21180 gagccattgt ccaagacctg ggttgcggac cctatttttt gggaacctac gataagcgct 21240 tcccggggtt catggccccc gataagctcg cctgtgccat tgtaaatacg gccggacgtg 21300 agacgggggg agagcactgg ttggctttcg gttggaaccc acgttctaac acctgctacc 21360 tttttgatcc ttttggattc tcggatgatc gtctcaaaca gatttaccag tttgaatatg 21420 agggtctcct gcgccgcagc gctcttgcta ccaaggaccg ctgtattacg ctggaaaaat 21480 ctacccagac cgtgcagggt ccccgttctg ccgcctgcgg acttttctgc tgcatgttcc 21540 ttcacgcctt tgtgcactgg cctgaccgtc ccatggacgg aaaccccacc atgaaattgc 21600 taactggagt gccaaacaac atgcttcatt ctcctaaagt ccagcccacc ctgtgtgaca 21660 atcaaaaagc actctaccat tttcttaata cccattcgcc ttattttcgc tcccatcgta 21720 cacacatcga aagggccact gcgttcgacc gtatggatgt tcaataatga ctcatgtaaa 21780 caacgtgttc aataaacatc actttatttt tttacatgta tcaaggctct gcattactta 21840 tttatttaca agtcgaatgg gttctgacga gaatcagaat gacccgcagg cagtgatacg 21900 ttgcggaact gatacttggg ttgccacttg aattcgggaa tcaccaactt gggaaccggt 21960 atatcgggca ggatgtcact ccacagcttt ctggtcagct gcaaagctcc aagcaggtca 22020 ggagccgaaa tcttgaaatc acaattagga ccagtgcttt gagcgcgaga gttgcggtac 22080 accggattgc agcactgaaa caccatcagc gacggatgtc tcacgcttgc cagcacggtg 22140 ggatctgcaa tcatgcccac atccagatct tcagcattgg caatgctgaa cggggtcatc 22200 ttgcaggtct gcctacccat ggcgggcacc caattaggct tgtggttgca atcgcagtgc 22260 agggggatca gtatcatctt ggcctgatcc tgtctgattc ctggatacac ggctctcatg 22320 aaagcatcat attgcttgaa agcctgctgg gctttactac cctcggtata aaacatcccg 22380 caggacctgc tcgaaaactg gttagctgca cagccggcat cattcacaca gcagcgggcg 22440 tcattgttag ctatttgcac cacacttctg ccccagcggt tttgggtgat tttggttcgc 22500 tcgggattct cctttaaggc tcgttgtccg ttctcgctgg ccacatccat ctcgataatc 22560 tgctccttct gaatcataat attgccatgc aggcacttca gcttgccctc ataatcattg 22620 cagccatgag gccacaacgc acagcctgta cattcccaat tatggtgggc gatctgagaa 22680 aaagaatgta tcattccctg cagaaatctt cccatcatcg tgctcagtgt cttgtgacta 22740 gtgaaagtta actggatgcc tcggtgctcc tcgtttacgt actggtgaca gatgcgcttg 22800 tattgttcgt gttgctcagg cattagttta aaagaggttc taagttcgtt atccagcctg 22860 tacttctcca tcagcagaca catcacttcc atgcctttct cccaagcaga caccaggggc 22920 aagctaatcg gattcttaac agtgcaggca gcagctcctt tagccagagg gtcatcttta 22980 gcgatcttct caatgcttct tttgccatcc ttctcaacga tgcgcacggg cgggtagctg 23040 aaacccactg ctacaagttg cgcctcttct ctttcttctt cgctgtcttg actgatgtct 23100 tgcatgggga tatgtttggt cttccttggc ttctttttgg ggggtatcgg aggaggagga 23160 ctgtcgctcc gttccggaga cagggaggat tgtgacgttt cgctcaccat taccaactga 23220 ctgtcggtag aagaacctga ccccacacgg cgacaggtgt ttctcttcgg gggcagaggt 23280 ggaggcgatt gcgaagggct gcggtccgac ctggaaggcg gatgactggc agaacccctt 23340 ccgcgttcgg gggtgtgctc cctgtggcgg tcgcttaact gatttccttc gcggctggcc 23400 attgtgttct cctaggcaga gaaacaacag acatggaaac tcagccattg ctgtcaacat 23460 cgccacgagt gccatcacat ctcgtcctca gcgacgagga aaaggagcag agcttaagca 23520 ttccaccgcc cagtcctgcc accacctcta ccctagaaga taaggaggtc gacgcatctc 23580 atgacatgca gaataaaaaa gcgaaagagt ctgagacaga catcgagcaa gacccgggct 23640 atgtgacacc ggtggaacac gaggaagagt tgaaacgctt tctagagaga gaggatgaaa 23700 actgcccaaa acaacgagca gataactatc accaagatgc tggaaatagg gatcagaaca 23760 ccgactacct catagggctt gacggggaag acgcgctcct taaacatcta gcaagacagt 23820 cgctcatagt caaggatgca ttattggaca gaactgaagt gcccatcagt gtggaagagc 23880 tcagccgcgc ctacgagctt aacctctttt cacctcgtac tccccccaaa cgtcagccaa 23940 acggcacctg cgagccaaat cctcgcttaa acttttatcc agcttttgct gtgccagaag 24000 tactggctac ctatcacatc ttttttaaaa atcaaaaaat tccagtctcc tgccgcgcta 24060 atcgcacccg cgccgatgcc ctactcaatc tgggacctgg ttcacgctta cctgatatag 24120 cttccttgga agaggttcca aagatcttcg agggtctggg caataatgag actcgggccg 24180 caaatgctct gcaaaaggga gaaaatggca tggatgagca tcacagcgtt ctggtggaat 24 240 tggaaggcga taatgccaga ctcgcagtac tcaagcgaag catcgaggtc acacacttcg 24300 catatcccgc tgtcaacctg ccccctaaag tcatgacggc ggtcatggac cagttactca 24360 ttaagcgcgc aagtcccctt tcagaagaca tgcatgaccc agatgcctgt gatgagggta 24420 aaccagtggt cagtgatgag cagctaaccc gatggctggg caccgactct cccagggatt 24480 tggaagagcg tcgcaagctt atgatggccg tggtgctggt taccgtagaa ctagagtgtc 24540 tccgacgttt ctttaccgat tcagaaacct tgcgcaaact cgaagagaat ctgcactaca 24600 cttttagaca cggctttgtg cggcaggcat gcaagatatc taacgtggaa ctcaccaacc 24660 tggtttccta catgggtatt ctgcatgaga atcgcctagg acaaagcgtg ctgcacagca 24720 ccctgaaggg ggaagcccgc cgtgattaca tccgcgattg tgtctatctg tacctgtgcc 24780 acacgtggca aaccggcatg ggtgtatggc agcaatgttt agaagaacag aacttgaaag 24840 agcttgacaa gctcttacag aaatctctta aggttctgtg gacagggttc gacgagcgca 24900 ccgtcgcttc cgacctggca gacctcatct tcccagagcg tctcagggtt actttgcgaa 24960 acggattgcc tgactttatg agccagagca tgcttaacaa ttttcgctct ttcatcctgg 25020 aacgctccgg tatcctgccc gccacctgct gcgcactgcc ctccgacttt gtgcctctca 25080 cctaccgcga gtgccccccg ccgctatgga gtcactgcta cctgttccgt ctggccaact 25 140 atctctccta ccactcggat gtgatcgagg atgtgagcgg agacggcttg ctggagtgtc 25200 actgccgctg caatctgtgc acgccccacc ggtccctagc ttgcaacccc cagttgatga 25260 gcgaaaccca gataataggc acctttgaat tgcaaggccc cagcagccaa ggcgatgggt 25320 cttctcctgg gcaaagttta aaactgaccc cgggactgtg gacctccgcc tacttgcgca 25380 agtttgctcc ggaagattac cacccctatg aaatcaagtt ctatgaggac caatcacagc 25440 ctccaaaggc cgaactttcg gcctgcgtca tcacccaggg ggcaattctg gcccaattgc 25500 aagccatcca aaaatcccgc caagaatttc tactgaaaaa gggtaagggg gtctaccttg 25560 acccccagac cggcgaggaa ctcaacacaa ggttccctca ggatgtccca acgacgagaa 25620 aacaagaagt tgaaggtgca gccgccgccc ccagaagata tggaggaaga ttgggacagt 25680 caggcagagg aggcggagga ggacagtctg gaggacagtc tggaggaaga cagtttggag 25740 gaggaaaacg aggaggcaga ggaggtggaa gaagtaaccg ccgacaaaca gttatcctcg 25800 gctgcggaga caagcaacag cgctaccatc tccgctccga gtcgaggaac ccggcggcgt 25860 cccagcagta gatgggacga gaccggacgc ttcccgaacc caaccagcgc ttccaagacc 25920 ggtaagaagg atcggcaggg atacaagtcc tggcgggggc ataagaatgc catcatctcc 25980 tgcttgcatg agtgcggggg caacatatcc ttcacgcggc gctacttgct attccaccat 26040 ggggtgaact ttccgcgcaa tgttttgcat tactaccgtc acctccacag cccctactat 26100 agccagcaaa tcccggcagt ctcgacagat aaagacagcg gcggcgacct ccaacagaaa 26160 accagcagcg gcagttagaa aatacacaac aagtgcagca acaggaggat taaagattac 26220 agccaacgag ccagcgcaaa cccgagagtt aagaaatcgg atctttccaa ccctgtatgc 26280 catcttccag cagagtcggg gtcaagagca ggaactgaaa ataaaaaacc gatctctgcg 26340 ttcgctcacc agaagttgtt tgtatcacaa gagcgaagat caacttcagc gcactctcga 26400 ggacgccgag gctctcttca acaagtactg cgcgctgact cttaaagagt aggcagcgac 26460 cgcgcttatt caaaaaaggc gggaattaca tcatcctcga catgagtaaa gaaattccca 26520 cgccttacat gtggagttat caaccccaaa tgggattggc ggcaggcgcc tcccaggact 26580 actccacccg catgaattgg ctcagcgccg ggccttctat gatttctcga gttaatgata 26640 tacgcgccta ccgaaaccaa atacttttgg aacagtcagc tcttaccacc acgccccgcc 26700 aacaccttaa tcccagaaat tggcccgccg ccctagtgta ccaggaaagt cccgctccca 26760 ccactgtatt acttcctcga gacgcccagg ccgaagtcca aatgactaat gcaggtgcgc 26820 agttagctgg cggctccacc ctatgtcgtc acaggcctcg gcataatata aaacgcctga 26880 tgatcagagg ccgaggtatc cagctcaacg acgagtcggt gagctctccg cttggtctac 26940 gaccagacgg aatctttcag attgccggct gcgggagatc ttccttcacc cctcgtcagg 27000 ctgttctgac tttggaaagt tcgtcttcgc aaccccgctc gggcggaatc gggaccgttc 27060 aatttgtgga ggagtttact ccctctgtct acttcaaccc cttctccgga tctcctgggc 27120 attacccgga cgagttcata ccgaacttcg acgcgattag cgagtcagtg gacggctacg 27180 attgatgtct ggtgacgcgg ctgagctatc tcggctgcga catctagacc actgccgccg 27240 ctttcgctgc tttgcccggg aactcattga gttcatctac ttcgaactcc ccaaggatca 27300 ccctcaaggt ccggcccacg gagtgcggat ttctatcgaa ggcaaaatag actctcgcct 27360 gcaacgaatt ttctcccagc ggcccgtgct gatcgagcga gaccagggaa acaccacggt 27420 ttccatctac tgcatttgta atcaccccgg attgcatgaa agcctttgct gtcttatgtg 27480 tactgagttt aataaaaact gaattaagac tctcctacgg actgccgctt cttcaacccg 27540 gattttacaa ccagaagaac gaaacttttc ctgtcgtcca ggactctgtt aacttcacct 27600 ttcctactca caaactagaa gctcaacgac tacaccgctt ttccagaagc attttcccta 27660 ctaatactac tttcaaaacc ggaggtgagc tccaaggtct tcctacagaa aacccttggg 27720 tggaagcggg ccttgtagtg ctaggaattc ttgcgggtgg gcttgtgatt attctttgct 27780 acctatacac accttgcttc actttcttag tggtgttgtg gtattggttt aaaaaatggg 27840 gcccatacta gtcttgcttg ttttactttc gcttttggaa ccgggttctg ccaattacga 27900 tccatgtcta gacttcgacc cagaaaactg cacacttact tttgcacccg acacaagccg 27960 catctgtgga gttcatcgcc tctcttacga acttggcccc caacgacaaa aatttacctg 28020 catggtggga atcaacccca tagttatcac ccagcaaagt ggagatacta agggttgcat 28080 tcactgctcc tgcgattcca tcgagtgcac ctacaccctg ctgaagaccc tatgcggcct 28140 aagagacctg ctaccaatga attaaaaaat gattaataaa aaatcactta cttgaaatca 28200 gcaataaggt ctctgttgaa attttctccc agcagcacct cacttccctc ttcccaactc 28260 tggtattcta aaccccgttc agcggcatac tttctccata ctttaaaggg gatgtcaaat 28320 tttagctcct ctcctgtacc cacaatcttc atgtctttct tcccagatga ccaagagagt 28380 ccggctcagt gactccttca accctgtcta cccctatgaa gatgaaagca cctcccaaca 28440 cccctttata aacccagggt ttatttcccc aaatggcttc acacaaagcc caaacggagt 28500 tcttacttta aaatgtttaa ccccactaac aaccacaggc ggatctctac agctaaaagt 28560 gggaggggga cttacagtgg atgacaccaa cggttttttg aaagaaaaca taagtgccac 28620 cacaccactc gttaagactg gtcactctat aggtttacca ctaggagccg gattgggaac 28680 gaatgaaaat aaactttgta tcaaattagg acaaggactt acattcaatt caaacaacat 28740 ttgcattgat gacaatatta acaccttatg gacaggagtc aaccccaccg aagccaactg 28800 tcaaatcatg aactccagtg aatctaatga ttgcaaatta attctaacac tagttaaaac 28860 tggagcacta gtcactgcat ttgtttatgt tataggagta tctaacaatt ttaatatgct 28920 aactacacac agaaatataa attttactgc agagctgttt ttcgattcta ctggtaattt 28980 actaactaga ctctcatccc tcaaaactcc acttaatcat aaatcaggac aaaacatggc 29040 tactggtgcc attactaatg ctaaaggttt catgcccagc acgactgcct atcctttcaa 29100 tgataattct agagaaaaag aaaactacat ttacggaact tgttactaca cagctagtga 29160 tcgcactgct tttcccattg acatatctgt catgcttaac cgaagagcaa taaatgacga 29220 gacatcatat tgtattcgta taacttggtc ctggaacaca ggagatgccc cagaggtgca 29280 aacctctgct acaaccctag tcacctcccc atttaccttt tactacatca gagaagacga 29340 ctgacaaata aagtttgcga tcgctaccct gcaggaactt gtttatttga aaatcaattc 29400 acaaaatccg agtagttatt ttgcctcccc cttcccattt aacagaatac accaatctct 29460 ccccacgcac agctttaaac atttggatac cattagatat agacatggtt ttagattcca 29520 cattccaaac agtttcagag cgagccaatc tggggtcagt gatagataaa aatccatcgg 29580 gatagtcttt taaagcgctt tcacagtcca actgctgcgg atgcgactcc ggagtctgga 29640 tcacggtcat ctggaagaag aacgatggga atcataatcc gaaaacggta tcggacgatt 29700 gtgtctcatc aaacccacaa gcagccgctg tctgcgtcgc tccgtgcgac tgctgtttat 29760 gggatcaggg tccacagtgt cctgaagcat gattttaata gcccttaaca tcaactttct 29820 ggtgcgatgc gcgcagcaac gcattctgat ttcactcaaa tctttgcagt aggtacaaca 29880 cattattaca atattgttta ataaaccata attaaaagcg ctccagccaa aactcatatc 29940 tgatataatc gcccctgcat gaccatcata ccaaagttta atataaatta aatgacgttc 30000 cctcaaaaac acactaccca catacatgat ctcttttggc atgtgcatat taacaatctg 30060 tctgtaccat ggacaacgtt ggttaatcat gcaacccaat ataaccttcc ggaaccacac 30120 tgccaacacc gctcccccag ccatgcattg aagtgaaccc tgctgattac aatgacaatg 30180 aagaacccaa ttctctcgac cgtgaatcac ttgagaatga aaaatatcta tagtggcaca 30240 acatagacat aaatgcatgc atcttctcat aatttttaac tcctcaggat ttagaaacat 30300 atcccaggga ataggaagct cttgcagaac agtaaagctg gcagaacaag gaagaccacg 30360 aacacaactt acactatgca tagtcatagt atcacaatct ggcaacagcg ggtggtcttc 30420 agtcatagaa gctcgggttt cattttcctc acaacgtggt aactgggctc tggtgtaagg 30480 gtgatgtctg gcgcatgatg tcgagcgtgc gcgcaacctt gtcataatgg agttgcttcc 30540 tgacattctc gtattttgta tagcaaaacg cggccctggc agaacacact cttcttcgcc 30600 ttctatcctg ccgcttagcg tgttccgtgt gatagttcaa gtacaaccac actcttaagt 30660 tggtcaaaag aatgctggct tcagttgtaa tcaaaactcc atcgcatcta atcgttctga 30720 ggaaatcatc caagcaatgc aactggattg tgtttcaagc aggagaggag agggaagaga 30780 cggaagaacc atgttaattt ttattccaaa cgatctcgca gtacttcaaa ttgtagatcg 30840 cgcagatggc atctctcgcc cccactgtgt tggtgaaaaa gcacagctag atcaaaagaa 30900 atgcgatttt caaggtgctc aacggtggct tccagcaaag cctccacgcg cacatccaag 30960 aacaaaagaa taccaaaaga aggagcattt tctaactcct caatcatcat attacattcc 31020 tgcaccattc ccagataatt ttcagctttc cagccttgaa ttattcgtgt cagttcttgt 31080 ggtaaatcca atccacacat tacaaacagg tcccggaggg cgccctccac caccattctt 31140 aaacacaccc tcataatgac aaaatatctt gctcctgtgt cacctgtagc gaattgagaa 31200 tggcaacatc aattgacatg cccttggctc taagttcttc tttaagttct agttgtaaaa 31260 actctctcat attatcacca aactgcttag ccagaagccc cccgggaaca agagcagggg 31320 acgctacagt gcagtacaag cgcagacctc cccaattggc tccagcaaaa acaagattgg 31380 aataagcata ttgggaaccg ccagtaatat catcgaagtt gctggaaata taatcaggca 31440 gagtttcttg taaaaattga ataaaagaaa aatttgccaa aaaaacattc aaaacctctg 31500 ggatgcaaat gcaataggtt accgcgctgc gctccaacat tgttagtttt gaattagtct 31560 gcaaaaataa aaaaaaaaac aagcgtcata tcatagtagc ctgacgaaca gatggataaa 31620 tcagtctttc catcacaaga caagccacag ggtctccagc tcgaccctcg taaaacctgt 31680 catcatgatt aaacaacagc accgaaagtt cctcgcggtg accagcatga ataattcttg 31740 atgaagcata caatccagac atgttagcat cagttaacga gaaaaaacag ccaacatagc 31800 ctttgggtat aattatgctt aatcgtaagt atagcaaagc cacccctcgc ggatacaaag 31860 taaaaggcac aggagaataa aaaatataat tatttctctg ctgctgttca ggcaacgtcg 31920 cccccggtcc ctctaaatac acatacaaag cctcatcagc catggcttac cagacaaagt 31980 acagcgggca cacaaagcac aagctctaaa gtgactctcc aacctctcca caatatatat 32040 atacacaagc cctaaactga cgtaatggga gtaaagtgta aaaaatcccg ccaaacccaa 32 100 cacacacccc gaaactgcgt caccagggaa aagtacagtt tcacttccgc aatcccaaca 32160 ggcgtaactt cctctttctc acggtacgtg atatcccact aacttgcaac gtcattttcc 32220 cacggtcgca ccgccccttt tagccgttaa ccccacagcc aatcaccaca cgatccacac 32280 tttttaaaat cacctcattt acatattggc accattccat ctataaggta tattatatag 32340 ataga 32345

Claims (22)

As replication competent oncolytic group B adenovirus EnAd,
Two or more transgenes,
DNA sequence encoding a first transgene comprising the B7-1 protein, and
An additional transgene encoding an anti-CD3 antibody or a binding fragment thereof,
The transgene is located at the same position between the stop codon of the adenovirus gene L5 and the poly-recognition site and the stop codon of the gene E4 and the poly A recognition site under the control of a major later promoter endogenous to the virus Replicable Tumor Cells Collapse B Group Adenovirus. 3. The virus according to claim 1, wherein the virus has the formula (I)
5 'ITR-B ₁ -B _A -B ₂ -B _X -B _B -B _Y -B ₃ -3'ITR (I)
B ₁ is a bond or comprises E1A, E1B or E1A-E1B;
B _A is E2B-L1-L2-L3-E2A-L4;
B ₂ is a bond, or E3 or a transgene;
B _X is a bond or a DNA sequence comprising a restriction site, one or more transfer genes, or both;
B _B comprises L5;
B _Y comprises a transgene cassette comprising a combination of a regulatory element or regulatory element with a transgene encoding said B7-1 protein;
B ₃ is a bond, or includes E 4. 3. The method of claim 2, wherein the regulatory element is a high-efficiency self-cleavable peptide. 4. The clone of claim 3, wherein the sequence is selected from P2A, T2A, F2A and E2A. 5. The method according to any one of claims 1 to 4, wherein the at least one protein encoded by the virus is suitable for expression on the surface of cancer cells infected with the protein, wherein the protein is not a fusion protein, virus. 6. The virus according to any one of claims 1 to 5, wherein the virus encodes a plurality of proteins for surface expression on infected cancer cells. 7. The replication-competent tumor cell decay virus according to claim 5 or 6, wherein the protein is treated and expressed independently at physically discrete locations on the cancer cell membrane. 8. A replication-competent tumor cell decay virus according to any one of claims 1 to 7, wherein the antibody or binding fragment further comprises a transmembrane domain or GPI anchor that allows the cell membrane-anchored form. 9. A replication-competent tumor cell decay virus according to any one of claims 1 to 8, wherein said anti-CD3 is an scFv antibody fragment. 10. The replication-competent tumor cell decay virus according to any one of claims 1 to 9, wherein the B7-1 protein is a full-length protein. 11. A replication-competent tumor cell decay virus according to any one of claims 1 to 10, wherein the B7-1 protein comprises a transmembrane domain or a GPI anchor. 11. The replication-competent tumor cell decay virus according to any one of claims 1 to 10, wherein said B7-1 protein comprises a transmembrane domain from B7 protein. 13. The method of any one of claims 1 to 12, wherein the virus comprises a third transgene encoding a polypeptide selected from the group comprising cytokines, chemokines, ligands, antagonistic antibody molecules and functional antibody molecules A replicable tumor cell collapsing virus. 14. The replication-competent tumor cell decay virus according to any one of claims 1 to 13, wherein the B7-1 protein is human. 15. The replication-competent tumor cell-degrading virus of claim 14, wherein the B7-1 protein has the sequence shown in SEQ ID NO: 1 or a sequence at least 95% identical thereto. 16. The replication-competent tumor cell-degrading virus according to any one of claims 1 to 15, wherein the antibody molecule or binding fragment thereof comprises an anti-human CD3 antigen binding domain. 17. The replication-competent tumor cell decay virus according to claim 16, wherein said binding fragment has the sequence shown in SEQ ID NO: 15 or 99. 9. The cloned tumor cell decay adenovirus according to claim 1, comprising SEQ ID NO: 96. 18. A pharmaceutical composition comprising a replicable tumor cell decay virus according to any one of claims 1 to 18 and a pharmaceutically acceptable excipient. 19. A cloned tumor cell-degrading virus according to any one of claims 1 to 18 for use in therapy, or a pharmaceutical composition according to claim 19. The use of a replication-competent tumor cell-degrading virus according to any one of claims 1 to 18 or a composition according to claim 19 for use in the manufacture of a medicament for the treatment of cancer. 22. The virus or pharmaceutical composition according to claim 21, wherein the cancer is selected from colorectal cancer, lung cancer, bladder cancer, kidney cancer, pancreatic cancer, liver cancer, head and neck cancer, breast cancer and ovarian cancer.

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